Sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same

ABSTRACT

Compounds having a metalloproteinase inhibitory activity, represented by the formula (I), its optically active isomers, their pharmaceutically acceptable salts, or hydrates thereof.

This application is a division of Ser. No. 09/120,197 filed Jul. 22, 1998.

TECHNICAL FIELD

This application relates to sulfonated amino acid derivatives and metalloproteinase inhibitors containing the same.

BACKGROUND ART

An extracellular matrix consists of collagen, proteoglycan, etc., has a function to support tissues, and plays a role in a maintaining of a cell functions, for example propagation, differentiation, adhesion, or the like. Matrix metalloproteinases (MMP) such as gelatinase, stromelysin, collagenase, and the like have an important role in degradation of an extracellular matrix, and these enzymes work for growth, tissue remodeling, etc. under physiological conditions. Therefore, it is considered that these enzymes participate in progression of various kind of diseases involving breakdown and fibrosis of tissues, such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (for example, HIV infection). At the present time, it is not clear which enzyme participates in the above diseases seriously, but it is considered that these enzymes at least participate in tissue breakdown. As metalloproteinase inhibitors of amino acid derivatives, for example hydroxamic acid derivatives of amino acids (JP-A-6-2562939), carboxylic acid derivatives of amino acid and/or their hydroxamic acid derivatives (W095135276), etc. are disclosed.

DISCLOSURE OF INVENTION

If it is able to inhibit the activity of MMP, it is considered that MMP inhibitors contribute to an improvement and prevention of the above diseases caused by or related to its activity. Therefore, development of MMP inhibitors has long been desired.

In the above situation, the inventors of the present invention found that a kind of sulfonamide derivatives have strong activity to inhibit MMP.

The present invention relates to a composition for inhibiting metalloproteinase which contains a compound of the formula I:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R⁴ is a bond, —(CH₂)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R^(A))—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂NH—, —SO₂—NH—N═CH—, or tetrazol-diyl; R⁵ is optionally substituted lower alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R^(A) is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R² is hydrogen atom when Y is —NHOH, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

Mentioned in more detail, the invention relates to the following a)-b), 1)-16), and A)-C).

a) A composition for inhibiting metalloproteinase which contains a compound of the formula I:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R⁴ is a bond, —(CH₂)m—, —CH═CH13 , —C≡C—, 13 CO—, —CO—NH—, —N═N—, —N(R^(A))—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂NH—, —SO₂—NH—N═CH—, or tetrazol-diyl; R⁵ is optionally substituted lower alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R^(A) is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R² is hydrogen atom when Y is —NHOH, R⁵ is optionally substituted aryl or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is —CO—NH— or —NH—CO—, R⁵ is optionally substituted aryl or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is tetrazol-diyl, R⁵ is lower alkyl, aryl substituted by lower alkyl or optionally substituted aryl, or heteroaryl substituted by lower alkyl or optionally substituted aryl when R³ is optionally substituted arylene and R⁴ is a bond, both of R³ and R⁴ are not a bond at the same time, and R⁴ is not —O— when R³ is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

b) A composition for inhibiting metalloproteinase as mentioned above, which is a composition for inhibiting type-IV collagenase.

Preferred embodiment of the present invention are as follows. 1) A compound of the formula 1:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond, optionally substituted arylene, or optionally substituted heteroarylene; R⁴ is a bond, —(CH₂)m—, —CH═CH—, —C≡C—, —CO—, —CO—NH—, —N═N—, —N(R^(A))—, —NH—CO—NH—, —NH—CO—, —O—, —S—, —SO₂NH—, —SO₂—NH—N═CH—, or tetrazol-diyl; R⁵ is optionally substituted lower alkyl, optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or an optionally substituted non-aromatic heterocyclic group; R^(A) is hydrogen atom or lower alkyl; Y is —NHOH or —OH; and m is 1 or 2; provided R² is hydrogen atom when Y is —NHOH, R⁵ is optionally substituted aryl or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is —CO—NH— or —NH—CO— (when R³ is phenylene and R⁴ is —CO—NH—, R¹ is not methyl or phenyl and R⁵ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl), R⁵ is lower alkyl, optionally substituted aryl, or optionally substituted heteroaryl when R³ is optionally substituted arylene or optionally substituted heteroarylene and R⁴ is tetrazol-diyl, R⁵ is lower alkyl, aryl substituted with lower alkyl or optionally substituted aryl, or heteroaryl substituted with lower alkyl or optionally substituted aryl when R³ is optionally substituted arylene and R⁴ is a bond, both of R³ and R⁴ are not a bond at the same time, and R⁴ is not —O— when R³ is optionally substituted arylene or optionally substituted heteroarylene, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

2) A compound of the formula II:

wherein R⁶ is —CH═CH—, —C≡C—, —N═N—, —NH—CO—NH—, —S—, —SO₂NH—, or —SO₂—NH—N═CH—; R⁷ is optionally substituted aryl or optionally substituted heteroaryl; R⁸ and R⁹ are each independently hydrogen atom, lower alkoxy, or nitro; R¹, R², and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

3) A compound of the formula III:

wherein R¹⁰ is —(CH₂)m—, —CO—, —CO—NH—, —N(R^(A))—, —NHCO—, or tetrazol-diyl; m is 1 or 2; R¹, R², R⁷, R⁸, R⁹, R¹, and Y are as defined above, provided R¹ is not methyl or phenyl and R⁷ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl when R¹⁰ is —NH— CO—, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

4) A compound of the formula IV:

wherein R¹¹ is a bond, —CH═CH—, or —C≡C—; X is oxygen atom or sulfur atom, R¹, R², R⁷, and Y are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

5) A compound of the formula I′:

wherein R¹′ is benzyl, (indol-3-yl)methyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (1-acetylindol-3-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, (1-alkoxycarbonyl-3-yl)methyl (for example ethoxycarbonylmethyl), or i-propyl; R²′ is hydrogen atom, methyl, 4-aminobutyl, or benzyl; R³′ is 1,4-phenylene; R⁴′ is —O—; R⁵′ is phenyl or 4-hydroxy-phenyl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

6) A compound of the formula I″:

wherein R¹″ is 4-thiazolylmethyl, (indol-3-yl)methyl, (5-methoxyindol-3-yl)methyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-biphenylylmethyl, 2,2,2-trifluoroethyl, 2-phenylethyl, benzyl, i-propyl, 4-nitrobenzyl, 4-fluorobenzyl, cyclohexylmethyl, (1-methylindol-3-yl)methyl, (5-methylindol-3-yl)methyl, (5-fluoroindol-3-yl)methyl, (pyridin-4-yl)methyl, (benzothiazol-2-yl)methyl, (phenyl)(hydroxy)methyl, phenyl, carboxymethyl, 2-carboxyethyl, hydroxymethyl, phenylmethoxymethyl, 4-carboxybenzyl, (benzimidazol-2-yl)methyl, (1-methylsulfonylindol-3-yl)methyl, or (1-ethoxycarbonylindol-3-yl)methyl; R²″ is hydrogen atom; R³″ is 1,4-phenylene; R⁴″ is a bond; R⁵″ is phenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-fluorophenyl, 4-methylthiophenyl, 4-biphenylyl, 2-thienyl, benzoxazol-2-yl, benzothiazol-2-yl, or tetrazol-2-yl; and Y is as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

7) A compound of the formula V:

wherein R¹² is —CH═CH— or —C≡C—; R¹, R², R⁷, R⁸, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof

8) A compound of the formula VI:

wherein R², R⁸, and R⁹ are as defined above, R¹³ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R¹⁴ is optionally substituted aryl, or optionally substituted heteroaryl; provided R¹³ is not methyl or phenyl and R¹⁴ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

9) A compound of the formula VII:

wherein R¹, R², R⁷, R⁸, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

10) A compound of the formula VIII:

wherein R¹, R², R⁷, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

11) A compound of the formula VIII:

wherein R¹, R², R⁷, R⁸, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

12) A compound of the formula X:

wherein R¹² is —CH═CH— or —C≡C—; R¹, R⁷, R⁸, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

13) A compound of the formula XI:

wherein R⁸, R⁹, R¹³, and R¹⁴ are as defined above, provided R¹³ is not methyl or phenyl and R¹⁴ is not 2-chlorophenyl, 4-chlorophenyl, or 2,4-dichlorophenyl, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

14) A compound of the formula XII:

wherein R¹, R⁷, R⁸, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

15) A compound of the formula XIII:

wherein R¹, R⁷, and R¹¹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

16) A compound of the formula XIV:

wherein R¹, R⁷, R⁸, and R⁹ are as defined above, its optically active substance, their pharmaceutically acceptable salt, or hydrate thereof.

A compound of the invention is more specifically illustrated below:

A) The compound of any one of above 1) to 16), wherein R¹, R¹′, R¹″, and R¹³ are i-propyl, benzyl, or (indol-3-yl) methyl.

B) The compound of any one of above 1) to 4) and 7) to 16), wherein R⁵, R⁷, and R¹⁴ are phenyl optionally substituted with one or more substituents selected from the group consisting of alkoxy, alkylthio, and alkyl.

C) The compound of any one of above 1) to 16), wherein a configuration of asymmetric carbon atoms bonding with R¹, R¹′, R¹″, and R¹³ is R configuration.

Further, this invention relates to a pharmaceutical composition, a composition for inhibiting metalloproteinase, and a composition for inhibiting type IV collagenase which contain the compound above 1) to 16) and A) to C)

All of compounds of above 1) to 16) and A) to C) have strong metalloproteinase inhibitory activity, and the following compound is more preferable:

1) A compound wherein R¹ is i-propyl, benzyl, or (indol-3-yl) methyl, R² is hydrogen atom, R³ is 1,4-phenylene, R⁴ is —C≡C—, and R⁵ is optionally substituted phenyl.

2) A compound wherein R¹ is i-propyl, benzyl, or (indol-3-yl) methyl, R² is hydrogen atom, R³ is optionally substituted 2,5-thiophen-diyl, R⁴ is —C≡C—, and R⁵ is optionally substituted phenyl.

3) A compound wherein R¹ is i-propyl, benzyl, or (indol-3-yl)methyl, R² is hydrogen atom, R³ is 1,4-phenylene, R⁴ is tetrazol-diyl, and R⁵ is optionally substituted phenyl.

The term “alkyl” herein used means C₁-C₁₀ straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, tert-pentyl, and the like.

The term “lower alkyl” herein used means C₁-C₆ straight or branched chain alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, and the like.

The term “C₃-C₈ cycloalkyl” herein used is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term “aryl” herein used means monocyclic or condensed ring aromatic hydrocarbons. Examples of the aryl are phenyl, naphthyl, and the like.

The term “aralkyl” herein used means the above mentioned alkyl substituted by the above mentioned aryl at any possible position. Examples of the aralkyl are benzyl, phenethyl, phenylpropyl (e.g., 3-phenylpropyl), naphthylmethyl (α-naphthylmethyl), anthrylmethyl (9-anthrylmethyl), and the like. Benzyl is preferred. The aryl part may optionally be substituted.

The term “heteroaryl” herein used means a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring and may be fused with a carbocyclic ring or other heterocyclic ring at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl), indolyl (e.g., 2-indolyl), carbazolyl (e.g., 3-carbazolyl), imidazolyl (e.g., 4- imidazolyl), pyrazolyl (e.g., 1-pyrazolyl), benzimidazolyl (e.g., 2-benzimidazolyl), indazolyl (e.g., 3-indazolyl), indolizinyl (e.g., 6-indolizinyl), pyridyl (e.g., 4-pyridyl), quinolyl (e.g., 5-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), acridinyl (e.g., 1-acridinyl), phenanthridinyl (e.g., 2-phenanthridinyl), pyridazinyl (e.g., 3-pyridazinyl), pyrimidinyl (e.g., 4-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), cinnolinyl (e.g., 3-cinnolinyl), phthalazinyl (e.g., 2-phthalazinyl), quinazolinyl (e.g., 2-quinazolinyl), isoxazolyl (e.g., 3-isoxazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), oxazolyl (e.g., 2-oxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), isothiazolyl (e.g., 3-isothiazolyl), benzisothiazolyl (e.g., 2-benzisothiazolyl), thiazolyl (e.g., 2-thiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), furyl (e.g., 3-furyl), benzofuryl (e.g., 3-benzofuryl), thienyl (e.g., 2-thienyl), benzothienyl (e.g., 2-benzothienyl), tetrazolyl, and the like. The aryl part of the above heteroaryl is optionally substituted.

The term “heteroarylalkyl” herein used means the above mentioned alkyl substituted with the above mentioned heteroaryl at any possible position. Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 5-thiazolyl-2-ethyl), indolylmethyl (e.g., 2-indolylmethyl), imidazolylmethyl (e.g., 4-imidazolylmethyl), benzothiazolylmethyl (e.g., 2-benzothiazolylmethyl), benzopyrazolylmethyl (e.g., 1-benzopyrazolylmethyl), benzotriazolylmethyl (e.g., 4-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 2-pyridylmethyl), and the like. The aryl part of the above heteroaryl is optionally substituted.

The term “arylene” herein used is exemplified by phenylene, naphthylene, and the like. Mentioned in more detail, it is exemplified by 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, and the like.

The term “heteroarylene” herein used is exemplified by thiophen-diyl, furan-diyl, pyridin-diyl, and the like, in more detail, by 2,5-thiophen-diyl, 2,5-furan-diyl, and the like.

The term “non-aromatic heterocyclic group” herein used means 5 to 6 membered non-aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in the ring, and may bind at any possible position. Examples of the non-aromatic heterocyclic group are morpholino, piperidino, pyrrolidino, and the like.

The term “alkoxy” herein used means alkoxy of which alkyl part is the above mentioned alkyl. Examples of the alkoxy are methoxy, ethoxy, propoxy, butoxy, pentyloxy, and the like.

The term “lower alkoxy” herein used means alkoxy of which alkyl part is the above mentioned lower alkyl. Examples of the lower alkoxy are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, and the like.

The term “halogen” herein used means fluoro, chloro, bromo, and iodo.

The term “alkylthio” herein used means alkylthio whose alkyl part is the above mentioned lower alkyl. Examples of the alkylthio are methylthio, ethylthio, and the like.

Substituents for “optionally substituted alkyl”, “optionally substituted C₃-C₈ cycloalkyl”, and “optionally substituted non-aromatic heterocyclic group” are hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), substituted or unsubstituted amino (e.g., methylamino, dimethylamino, and carbamoylamino), guanidino, phenyl, benzyloxy, and the like. These substituents are able to bind them at one or more of any possible positions.

Substituents for the aromatic ring of “optionally substituted aryl”, “optionally substituted aralkyl”, “optionally substituted heteroaryl”, “optionally substituted heteroarylalkyl”, “optionally substituted arylene”, and “optionally substituted heteroarylene” are, for example, hydroxy, alkoxy (e.g., methoxy and ethoxy), mercapto, alkylthio (e.g., methylthio), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl), halogen (e.g., fluoro, chloro, bromo, and iodo), carboxy, alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), nitro, cyano, haloalkyl (e.g., trifluoromethyl), aryloxy (e.g., phenyloxy) substituted or unsubstituted amino (e.g., methylamino, dimethylamino, diethylamino, and benzylidenamino), guanidino, alkyl (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, i-pentyl, neo-pentyl, and tert-pentyl), alkenyl (e.g., vinyl and propenyl), alkynyl (e.g., ethynyl and phenylethynyl), alkanoyl (e.g., formyl, acetyl, and propionyl), acyloxy (e.g., acetyloxy), acylamino, alkylsulfonyl (e.g., methylsulfonyl), phenyl, benzyl, an azo group (e.g., phenylazo), optionally substituted heteroaryl (e.g., 3-pyridyl), optionally substituted ureido (e.g., ureido and phenylureido), and the like. These substituents are able to bind to it at one or more of any possible position.

BEST MODE FOR CARRYING OUT THE INVENTION

Compounds (Ia) and (Ib) of the invention are able to be synthesized from the corresponding α-amino acids represented by the formula (XV) by means of the following 6 synthetic methods. Generally, it is possible to produce the compounds of the invention by means of the method A. Each classified type of the compounds is possible to be produced by means of methods the B to F. However, these methods are only examples to produce the compounds represented by the formula I. A compound represented by the formula I produced by any other method is included in this invention.

Method A: A general synthetic method of the compound represented by the formula I.

Method B: A synthetic method of the compound wherein and R³ is optionally substituted arylene or optionally substituted heteroarylene, R⁴ is —C≡C—, and R⁵ is optionally substituted aryl or optionally substituted heteroaryl.

Method C: A synthetic method of the compound wherein R³ is optionally substituted arylene or optionally substituted heteroarylene, R⁴ is a bond, and R⁵ is optionally substituted aryl or optionally substituted heteroaryl.

Method D: A synthetic method of the compound wherein R³ is optionally substituted arylene or optionally substituted heteroarylene, R⁴ is —CO—NH—, and R⁵ is optionally substituted aryl or optionally substituted heteroaryl.

Method E: A synthetic method of the compound wherein R³ is optionally substituted arylene or optionally substituted heteroarylene, R⁴ is tetrazol-diyl, and R⁵ is optionally substituted aryl or optionally substituted heteroaryl.

Method F: A synthetic method of the compound wherein R³ is optionally substituted arylene or optionally substituted heteroarylene, R⁴ is —CH═CH—, and R⁵ is optionally substituted aryl or optionally substituted heteroaryl.

Details of these methods are explained as follows.

wherein R¹, R², R³, R⁴, and R⁵ are as defined above, R¹⁵ is hydrogen atom or a carboxy protective group, R¹⁶ is a hydroxy protective group, and Hal is halogen.

Conversion of compound (XV) to compound (Ia-1) is sulfonation of an amino group of the compound (XV) (process 1). If necessary, after this reaction, N-alkylation, deprotection of a carboxyl protective group, etc. are carried out. Conversion of compound (Ia-1) to compound (Ib-1) is to obtain hydroxamic acid derivatives from carboxylic acid derivatives (process 2). To obtain compound (Ib-1) from compound (Ia-1), compound (Ia-1) may also be reacted with hydroxylamine having a hydroxyl protective group or its acidic salts to give compound (XVI) (process 3), followed by and deprotection (process 4). Conversion to sulfonyl derivatives and hydroxamic acid derivatives are able to be carried out according to an usual method. For example, an amino acid represented by the formula (XV) is reacted with a sulfonating agent such as sulfonyl halide represented by R⁵—R⁴—R³—SO₂Hal (R³, R⁴, and R⁵ are as defined above; and Hal is halogen) and then hydroxylamine. Each process will hereinafter be described in more detail.

(Process 1)

Some of amino acids represented by the formula (XV) or its acidic salts (e.g., hydrochloride, p-toluenesulfonate, and trifluoroacetate) which are starting materials are commercially available. The other are able to be synthesized in accordance with a method described in Zikkenkagakukoza, vol. 22, IV (nihonkagakukai), J. Med. Chem. 38, 1689-1700, 1995, Gary M. Ksander et. al., etc. some of sulfonating agents are commercially available and the other are synthesized in accordance with a method described Shin-zikkenkagakukoza, vol. 14, 1787, 1978, Synthesis 852-854, 1986, etc. A carboxyl protective group is exemplified by esters (e.g., methyl ester, tert-butyl ester and benzyl ester). Deprotection of this protective group may be carried out by hydrolysis with acid (e.g., hydrochloride and trifluoroacetic acid) or base (e.g., sodium hydroxide) depending on the type of the group, or by catalytic reduction, e.g., under 10% palladium-carbon catalyst condition. To obtain a compound (Ib-1), the esters may directly be converted to hydroxamic acid by the method of process 2. When a compound (XV) is an amino acid wherein R¹⁵ is hydrogen atom, preferable solvents for this sulfonylation are dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, or mixed solvents thereof. When a compound (XV) is an amino acid wherein R¹⁵ is a protective group such as an ester, a solvent for this sulfonylation is exemplified by the above solvents and mixed solvents of water-insoluble solvents (e.g., benzene and dichloromethane) and the above solvents. A base to be used in this sulfonylation is exemplified by organic bases such as triethylamine, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and the like. Usually this reaction can be carried out at ice-cooling to room temperature. When R¹, R³, R⁴, R⁵, or R¹⁵ of compound (Ia-1) contains a functional group(s) possibly interfering this sulfonylation (e.g., hydroxy, mercapto, amino, and guanidino), it can previously be protected in accordance with a method described in “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)) and then deprotected at an appropriate process. When R² is not hydrogen atom, compound (Ia-1) wherein R² is hydrogen atom is further reacted with haloalkyl (e.g., methyl iodide, and ethyl iodide) or haloaralkyl (e.g., benzyl chloride, and benzyl bromide) in dimethylformamide, tetrahydrofuran, dioxane, and the like at a temperature range of ice-cooling to 80° C., preferably ice-cooling to room temperature, for 3-10 hours, preferably 10-20 hours to give the desired N—R² derivative.

(Process 2)

A hydroxylamine is reacted with compound (Ia-1) or its reactive derivatives to give hydroxamic acid derivatives (Ib-1). A hydroxylamine is usually used as its acidic salts (e.g., hydrochloride, and phosphate, sulfate: commercially available) in the presence of a base. A base to be used in this reaction is exemplified by organic bases such as triethylamine, N, N-dimethylaniline, N-methylmorpholine, etc. and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. When compound (Ia-1) is used as a starting material of conversion to hydroxamic acid, this reaction is carried out in the presence of a peptide condensing agent (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N,N′-carbonyldiimidazole, or a mixture of one of the above agents with 1-hydroxybenzotriazole, N-hydroxy sucinicimide, etc.). A solvent for this reaction may be dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, water, and mixed solvent thereof This reaction is carried out at −20° C. to 40° C., preferably ice-cooling to room temperature, for 1 to 16 hours.

Acid anhydrides (especially, mixed acid anhydrides), acid halides, acid azides, and esters can be utilized in this reaction as a reactive derivative of compound (Ia-1). These reactive derivatives are produced by usual methods. For example, the acid anhydride derivatives can be produced by a reaction of compound (Ia-1) with acid halide derivatives (e.g., ethyl chlorocarbonate) in the presence of a base (e.g., triethylamine), and acid halide derivatives can be produced by a reaction of compound (Ia-1) with a halogenation agent (e.g., oxalylchloride, and thionylchloride). Ester derivatives may be inactive or active. Sulfonyl derivatives converted from a compound (XV) wherein R¹⁵ is a carboxyl protective groups (e.g., methyl, tert-butyl, and benzyl) at process 1 can be used as inactive esters without deprotection. Active esters can be produced by a reaction of compound (Ia-1), carbodiimide reagents (e.g., dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), and hydroxy derivatives corresponding to the active ester residue such as 1-hydroxybenzotriazole, N-hydroxysuccinimide, or the like. A reaction condition of conversion of the reactive derivatives of compound (Ia-1) to hydroxamic acid may be the same as that of conversion of compound (Ia-1) itself to hydroxamic acid. The reactions of processes 1 and 2 are able to continuously be carried out in one-pot reaction.

(Process 3)

A protected hydroxylamine to be used in this reaction includes O-benzylhydroxylamine, O-(p-methoxybenzyl)hydroxylamine, O-(tert-butyl)hydroxylamine, or the like. This reaction condition may be in the same manner as that of process 2.

(Process 4)

This process for deprotection is carried out by catalytic reduction, treatment with conc. hydrochloric acid, or treatment with trifluoroacetic acid to give the desired compound (Ib-1). The compounds of this invention (Ia-1) and (Ib-1) can be isolated and purified by usual separation methods and purification methods (e.g., chromatography, crystallization, etc.).

wherein R¹, R², R⁷, R¹⁵, and Hal are as defined above, R¹⁷ is optionally substituted aryl or optionally substituted heteroaryl.

Conversion of compound (XV) to compound (XVII) is performed by sulfonation of an amino group of compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XVII) to compound (XVIII) is performed by Heck reaction (K. Sonogashira, Y. Tohda, and N. Hagihara, Tetrahedron Lett., 4467(1975) etc.) wherein halogen of R¹⁷ is utilized to insert a triple bond (process 2). Conversion of compound (XVIII) to compound (Ia-2) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 3), which can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-2) to compound (Ib-2) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 4), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(Process 1)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 2)

Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an ethynyl group such as ethynylbenzene in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph₃P)₂Cl₂), a divalent copper reagent (e.g., CuI), and an organic base (e.g., triethylamine, and diisopropylethylamine) to give a desired compound (XVIII) (Heck reaction). This reaction is carried out at room temperature to 100° C., preferably room temperature to 80° C. This reaction is completed for 3 to 30 hours, preferably 10 to 20 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)), and then deprotected at an appropriate step.

(Process 3)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 4)

This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

wherein R¹, R², R⁷, R¹⁵, R¹⁷, and Hal are as defined above.

Conversion of compound (XVII) to compound (XIX) is performed by Suzuki reaction (M. J. Sharp and V. Shieckus, Tetrahedron Lett., 26, 5997 (1985) etc.) wherein halogen of R¹⁷ is utilized to introduce aryl or heteroaryl (process 1). Conversion of compound (XIX) to compound (Ia-3) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 2) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-3) to compound (Ib-3) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 3), and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(process 1)

Compound (XVII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(OH)₂ (otherwise B(Et)₂) group such as phenylboronic acid in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph₃P)₄) and a base (e.g., potassium carbonate, calcium carbonate, triethylamine, sodium methoxide etc.) to give the desired compound (XIX) (Suzuki reaction). This reaction is carried out at room temperature to 100° C., preferably room temperature to 80° C. This reaction is completed for 5 to 50 hours, preferably 15 to 30 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)) and then deprotected at an appropriate step.

(Process 2)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 3)

This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

wherein R¹, R², R⁷, R¹⁵, R¹⁷, and Hal are as defined above.

Conversion of compound (XV) to compound (XX) is sulfonation of an amino group of the compound (XV) (process 1) and this process may be carried out in the same manner as that described in process 1 of method A. Conversion of compound (XX) to compound (XXI) is reduction of a nitro group of R¹⁷ to an amino group (process 2) and this process can be carried out by catalytic reduction or other reduction using hydrochloric chloride—Fe, hydrochloric chloride—Sn, etc. Conversion of compound (XXI) to compound (XXII) is performed by usual amide bond formation reaction wherein an amino group of R¹⁷ is utilized (process 3). Conversion of compound (XXII) to compound (Ia-4) is N-alkylation, deprotection of a carboxyl protective group, etc. (process 4) of compound (XXII) and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-4) to compound (Ib-4) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 5) and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(process 1)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 2)

Compound (XX) is treated with hydrogen in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, etc. in the presence of a catalyst (e.g., Pd-C, PtO₂, Raney Ni etc.), under a no-pressure or pressured condition to give the desired compound (XXI). This reaction is carried out at a temperature under ice-cooling to 80° C., preferably room temperature to 50° C., and is completed for 1 to 10 hours, preferably 2 to 5 hours.

(Process 3)

Compound (XXI) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an acid halide (otherwise an active ester) group such as benzoyl chloride in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, dimethylsulfoxide, acetonitrile, xylene, toluene, benzene, dichloromethane, etc. in the presence of a base (e.g., triethylamine, N-methylmorpholine, potassium carbonate etc.) to give the desired compound (XXII). This reaction is carried out at a temperature under ice-cooling to 100° C., preferably room temperature to 60° C., and is completed for 3 to 30 hours, preferably 10 to 25 hours.

(Process 4)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 5)

This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

wherein R¹, R², R⁷, R¹⁵, R¹⁷, and Hal are as defined above.

Conversion of compound (XV) to compound (XXIII) is performed by sulfonating an amino group of the compound (XV) (process 1) in the same manner as that described in process 1 of method A. Conversion of compound (XXIII) to compound (XXIV) is done by the reduction wherein an ethenyl group of R¹⁷ is converted into an aldehyde group (process 2). Conversion of compound (XXIV) to compound (XXVI) is performed by a tetrazole ring formation reaction (processes 3 and 4). Conversion of compound (XXVI) to compound (Ia-5) is N-alkylation, deprotection of a carboxyl protective group, etc. of compound (XXVI) (process 5), and this process can be carried out in the same manner as that described in process 1 of method A. Conversion of compound (Ia-5) to compound (Ib-5) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 6), which can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(process 1)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 2)

A compound (XXIII) is treated with ozone in a solvent such as dichloromethane, ethyl acetate, methanol, etc. to form an ozonide, and then a reagent such as zinc-acetic acid, triethylphosphate, dimethylsulfide, etc. is added to this reaction mixture for reduction to give the desired aldehyde derivatives (XXIV) The reduction can also be carried out by catalytic hydrogenation. This reaction is carried out at −100° C. to room temperature, preferably −78° C. to a temperature under ice-cooling, and is completed for 0.5 to 10 hours, preferably 1 to 3 hours.

(Process 3)

A compound (XXIV) is reacted with benzensulfonylhydrazide in a solvent such as tetrahydrofuran, ether, etc. mixed with a solvent such as methanol, ethanol, etc. to give the desired compound (XXV). This reaction is carried out at a temperature under ice-cooling to 80° C., preferably room temperature to 50° C., and is completed for 3 to 30 hours, preferably 10 to 20 hours.

(Process 4)

Optionally substituted aryl or optionally substituted heteroaryl having amino group such as aniline is dissolved in a mixed solvent such as alcohol (e.g., ethanol) and water. To this mixture conc. hydrochloric acid and a diazotizing agent such as a sodium nitrite aqueous solution are added at −20° C. to 10° C., preferably 0° C. to 5° C., to give a diazonium salt. The reaction time is 5 min to 1 hr, preferably 10 to 30 min. This reaction mixture is added to a pyridine solution of compound (XXV) and allowed react for 1 to 10 hr, preferably 2 to 5 hr, at −30° C. to 50° C., preferably −15° C. to room temperature to give the desired compound (XXVI). When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)), and then deprotected at an appropriate step.

(Process 5)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 6)

This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

wherein R¹, R², R⁷, R¹⁵, R¹⁷, and Hal are as defined above.

Conversion of compound (IV) to compound (XXVII) is performed by Wittig reaction (G. Wittig et al., Chem. Berr. 87, 1318 (1954)) wherein an aldehyde group of R⁷ is utilized to introduce aryl or heteroaryl through a double bond (process 1). Conversion of compound (XXVII) to compound (Ia-6) is N-alkylation, deprotection, etc. of compound (XXVII) (process 2), and this process can be carried out the same similar as described in process 1 of method A. Conversion of compound (Ia-6) to compound (Ib-6) is that of carboxylic acid derivatives to hydroxamic acid derivatives (process 3), and this process can be carried out in the same manner as those described in processes 2 to 4 of method A. Each process will hereinafter be described in more detail.

(process 1)

Compound (XXIV) is reacted with ylide derivatives of optionally substituted aryl or optionally substituted heteroaryl such as Ph₃P═CHPh, etc., which is produced by an usual method, in a solvent such as toluene, xylene, tetrahydrofuran, ether, dimethylformamide, etc. at −100° C. to room temperature, preferably −78° C. to ice-cooling for 1 to 20 hours, preferably 1 to 5 hours, to give the desired compound (XXVII). When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of “Protective Groups in Organic Synthesis” (Theodora W. Green (John Wiley & Sons)), and deprotected at an appropriate step.

(Process 2)

This process may be carried out in the same manner as that described in process 1 of method A.

(Process 3)

This process may be carried out in the same manner as those described in processes 2 to 4 of method A.

The term “compound of the present invention” herein used includes pharmaceutically acceptable salt or hydrate of the compound. The salt is exemplified by a salt with alkali metals (e.g., lithium, sodium, and potassium), alkaline earth metals (e.g., magnesium and calcium), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid), or organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid, benzenesulfonic acid, and p-toluenesulfonic acid). These salts can be formed by the usual method.

The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.

The compound of the present invention has an excellent activity for inhibiting metalloproteinase, especially activity for inhibiting MMP, and inhibits matrix dissolution, as described in the following test example. Therefore, the compound of the present invention is useful to treat or prevent diseases which are caused by MMP and relative enzymes such as TNF-α converting enzyme, etc.

Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple-sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer.

When the compound of the present invention is administered to a person for treatment or prevention of the above diseases, they can be administered by oral administration such as powder, granules, tablets, capsules, pilulae, and liquid medicine, or by parenteral administration such as injections, suppository, percutaneous formulations, insufflation, or the like. An effective dose of the compound of the invention is formulated by being mixed with medicinal admixture such as excipient, penetrant, disintegrators, lubricant, and the like if necessary. When parenteral injection is prepared, the compound of the invention and an appropriate carrier are sterilized to prepare it.

An appropriate dosage varies with the conditions of the patients, an administration route, their age, their body weight and the like and should be determined by a physician in the end. In the case of oral administration, a daily dosage can generally be between 0.1-100 mg/kg/day, preferably 1-20 mg/kg/day. In the case of parenteral administration, the daily dosage can generally be between 0.01-10 mg/kg/day, preferably 0.1-1 mg/kg/day. The daily dosage can be administrated in one to several divisions.

The following examples are provided to further illustrate the present invention and are not to be constructed as limiting the scope thereof.

Abbreviations described below are used in the following examples. p-TsOH: p-toluenesulfonic acid

DMSO: dimethylsulfoxide

Me: methyl

^(t)Bu: tert-butyl

EXAMPLE 1 (METHOD A)

To a suspension of (R)-(+)-phenylalanine (compound XV-1, 1.65g (10 mmol)) in 50 ml of dimethylformamide and 35 ml of water was stirred and treated with 2.78 ml (20 mmol) of triethylamine under ice-cooling. Then, 2.52g(10 mmol) of 4-biphenylsulfonyl chloride in 10 ml of dimethylformamide was added dropwise to the mixture over 5 min. After the reaction mixture was stirred for 2 h at the same temperature, 1.35 g (10 mmol) of 1-hydroxybenzotriazole hydrate, 2.1 g (11 mmol) of 1-ethyl-3-(3-dimethylamiinopropyl)carbodiimide hydrochloride, 3.47 g (50 mmol) of hydroxylamine hydrochloride, and 7 ml (50 mmol) of triethylamine were added to the mixture. After being stirred for 16 h at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO₃, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl₃/MeOH=40/1 to 20/1 were collected to yield 1.70 g of compound (Ib-1-1) as a foam.

Yield 43%. mp. 169-170° C.

Elemental analysis (%) C₂₁H₂₀N₂O₄S Calcd. : C; 63.62, H; 5.08, N; 7.07, S; 8.09 Found: C;63.61, H; 5.12, N; 6.98, S; 8.06

IR υ max (cm⁻¹) (Nujol): 3365, 3295, 3266, 1674, 1320, 1159.

NMR (δ ppm) d₆-DMSO: 2.61 (dd, J=8.6, 13.4 Hz, 1H), 2.80 (dd, J=6.0, 13.6 Hz, 1H), 3.80 (m, 1H).

[α]_(D):+18.5±1.2 (c=0.503 %, 25° C., DMSO)

EXAMPLE 1′

Another synthetic method of compound (Ib-1-1)

Process 1

To a solution of (R)-phenylalanine benzyl ester tosylate (compound XV-1′, 2.5 g (5.85 mmol)) in 60 ml of dichloromethane was added triethylamine (1.8 ml, 12.87 mmol) and 4-biphenylsulfonyl chloride(1.63 g, 6.44 mmol) under ice-cooling. After being stirred for 2 h at room temperature, the reaction mixture was washed with 2N HCl, 5% NaHCO₃ and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CHCl₃/MeOH=40/1 to 20/1 were collected and crystallized from dichloromethane/hexane to give 2.32 g of

compound (Ia-1-1′).

Yield 84.1%. mp. 130-131° C.

Elemental analysis (%) C₂₈H₂₅NO₄S Calcd. : C; 71.32, H; 5.34, N; 2.97, S; 6.80 Found: C; 71.05, H; 5.41, N; 3.00, S; 6.81

IR υ max (cm⁻¹) (Nujol): 3352, 1732, 1341, 1190, 1163.

NMR (δ ppm) (CDCl₃): 3.06 (d, J=5.8 Hz, 2H), 4.30 (dt, J=6.0, 9.0 Hz, 1H), 4.89 (s, 2H), 5.12 (d, J=9.0 Hz, 1H), 6.98-7.81 (m, 14H).

[α]_(D): −16.4±1.1(c=0.506 %, 25° C., MeOH)

Process 2

A solution of compound (Ia-1-1′) (2.28 g) which was obtained process 1 in 50 ml of mixed solvents of methanol/ethyl acetate=1/1, was hydrogenated using 10 % Pd/C (200 mg) for 25 min. The reaction mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane/hexane to give 1.83 g of compound (Ia-1-1″).

Yield 99.1%. mp. 146-147° C.

Elemental analysis (%) C₂₁H₁₉NO₄S Calcd.: C; 66.12, H; 5.02, N; 3.67, S; 8.41 Found: C;65.97, H; 5.06, N; 3.61, S; 8.48

IR υ max (cm⁻¹) (Nujol): 3408, 3305, 1751, 1325, 1161, 1134.

NMR (δ ppm) (CDCl₃): 2.97 (dd, J=7.0, 13.8 Hz, 1H), 3.14 (dd, J=5.2, 14.0 Hz, 1H), 4.13 (m, 1H), 7.03-7.78 (m, 14H).

[α]_(D): −4.0±0.4(c=1.000%, 25° C., MeOH)

Process 3

To a solution of compound (Ia-1-1″, 1.0 g (2.62 mmol)) which was obtained process 2 in dichloromethane (20 ml) was added 0.33 ml (3.93 mmol) of oxalyl chloride and one drop of dimethylformamide. After being stirred for stirred for 1 h at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 10 ml of tetrahydrofuran. A solution of hydroxylamine hydrochloride (911 mg (13.1 mmol)) and NaHCO₃ 1.54 g (18.34 mmol) in 10ml of tetrahydrofuran and 10 ml of water was stirred for 5 min under ice-cooling. To the mixture was added the above solution of acid chloride in tetrahydrofuran and the resulting mixture was stirred for 30 min. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with 5% NaHCO₃, and water, and concentrated in vacuo to give compound (Ia-1) (969 mg).

Yield 93.3 %.

Process 4

To a solution of compound (Ia-1-1″, 2.0 g, 5.24 mmol) which was obtained process 2 in dimethylformamide (20 ml) was added 1-hydroxybenzotriazole hydrate (0.7 g, 5.24 mmol), N-methylmorpholine (2.9 ml, 26.2 mmol), 1-ethyl-3-(3-diisopropylamino) carbodiimide hydrochloride (8 mmol), and O-benzylhydroxylamine hydrochloride (1.67 g, 10.48 mmol), and the resulting mixture was stirred for 6 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO₃, and water, and concentrated in vacuo. The residue was subjected to silica gel column chromatography and the fractions eluting with CH₂Cl₂/hexane=1/1 were collected and recrystallized from dichloromethane/hexane to give 2.04 g of compound (XVI-1).

Yield 80%. mp. 171-173° C.

Elemental analysis (%) C₂₈H₂₆N₂O₄S Calcd.: C; 69.12, H; 5.39, N; 5.76, S; 6.59 Found :C; 68.85, H; 5.46, N; 5.76, S; 6.78

IR υ max (cm⁻¹) (Nujol) : 3248, 1661, 1594, 1333, 1163.

NMR (δ ppm) (CDCl₃): 2.85-3.60 (m, 2H), 3.86 (m, 1H), 4.77 (ABq-Apart, J=11.4 Hz, 1H), 4.82 (ABq-Bpart, J=11.4 Hz, 1H), 5.00 (m, 1H), 6.95-7.70 (m, 19H).

[α]_(D): −40.2±1.6 (c=0.505%, 25° C., DMSO)

Process 5

A solution of compound (XVI-1) (1.97 g) which was obtained process 4 in a 60 ml of mixed solvents of methanol/ethyl acetate=1/1 was hydrogenated using 10% Pd-C (200 mg) for 3.5 h. The reaction mixture was filtered off, and the filtrate was concentrated in vacuo. The residue was recrystallized from dichloromethane / hexane to give 1.35 g of compound (Ib-1-1).

Yield 84.4%.

EXAMPLE 2-91

The compounds which were shown in Tables 1 to 22 were synthesized in a manner similar to those described in Example 1′

TABLE 1 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 2

RS 173> 3258, 1650, 1377, 1348, 1163(Nujol) 2.87(dd, J=5.6, 14.2Hz, 1H), 2.98(dd, J=8.4, 14.2Hz, 1H), 4.02(dd, J=2.2, 8.6Hz, 1H), 7.24(d, J=2.0Hz, 1H), 8.83(d, J=2.2Hz), 1H) 3

R 203-206 3403, 3386, 3265, 1673 , 1320, 1162(Nujol) 2.72(dd, J=7.2, 13.8Hz, 1H), 2.97(dd, 7.0, 14.8Hz), 1H), 3.81(m, 1H), 4

RS — — — 5

RS 124-126 3277, 1669, 1397, 1322, 1159, 3.12(dd, J=10.3, 14.3Hz, 1H), 3.89(dd, J=3.3, 13.5Hz, 1H), 4.20(m, 1H), 5.90 (brs, 1H) 6

R 139-141 3262, 1663, 1322, 1157, 2.67(dd, J=9.2, 13.1Hz, 1H), 2.84(dd, J=5.3, 13.5Hz, 1H), 3.82(m, 1H) 7 CF₃CH₂—

R 167-169 3265, 1676, 1642, 1337, 1161(Nujol) 2.2-2.7(m, 2H), 3.99(t, J=7.0Hz, 1H) 8

RS 172-173 3403, 3261, 1669, 1321, 1160 1.68(m, 2H), 2.37(m, 2H), 3.64(t, J=6.9Hz, 1H) 9

R 144-146 3700-200br, 3264, 1635, 1342, 1164, 2.61(dd, J=9.4, 13.8Hz, 1H), 2.78(dd, J=6.0, 13.8Hz, 1H), 3.78(m, 1H), 7.43 (d, J=8.2Hz, 2H), 7.60(d, J=8.2Hz, 2H),

TABLE 2 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 10

R 116-118 3600-2400br, 3257, 1743, 1721, 1323, 1132, 2.60-2.82(m, 2H), 3.84(m, 1H), 7.00- 7.18(m, 5H), 7.62-7.80(m, 4H), 11

R 91-92 3700-2100br, 3176, 1664, 1320, 1143, 2.70-2.93(m, 2H), 2.82(s, 6H), 3.75(m, 1H), 12 (CH₃)₂CH—

R 178-179 3268, 1632, 1598, 1336, 1162 0.71(d, J=6.8Hz, 3H), 0.74(d, J=5.4Hz, 3H), 1. 73(m, 1H), 1.73(m, 1H), 3.22(m, 1H), 3.82(s, 3 H), 7.05(d, J=9.0Hz, 2H), 7.69(d, J=9.0Hz, 2H) 13

RS 184-185 3257, 1662, 1516, 1344, 1322, 1160, 2.80(dd, J=10.0, 13.8Hz, 1H), 2.92(dd, J=5.0, 12.8Hz, 1H), 3.90(dd, J=5.4, 9.6Hz, 1H), 14

RS 128-130 3258, 1669, 1509, 1322, 1157 2.62(dd, J=9.9, 13.5Hz, 1H), 2.78(dd, J=5.8, 13.0Hz, 1H), 3.77(t, J=6.2Hz, 1H), 15

R 165-166 3278, 2920, 1632, 1337, 1161 0.50-1.62(m, 13H), 3.56(t, J= 7.4Hz, 1H) 16

RS 172-173 3272, 1631, 1332, 1161 2.71(dd, J=7.9, 14.2Hz, 1H), 2.94(dd, J=6.9, 14.2Hz, 1H), 3.57(s, 3H), 3.83 (dd, J=7.0, 7.4Hz, 1H) 17

RS 144-146 3404, 1670, 1320, 1159 2.25(s, 3H), 2.67(dd, J=7.5, 14.2Hz, 1H), 2.95(dd, J=7.7, 14.6Hz, 1H), 3.81(dd, J=6.2, 14.2Hz, 1H)

TABLE 3 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 18

RS — 3420, 1670, 1592, 1321, 1159 2.72(dd, J=8.0, 14.0Hz, 1H), 2.90(dd, J=6.2, 14.2Hz, 1H), 3.82(m, 1H) 19

RS — — — 20

RS 154-158 3186, 1593, 1480, 1379 2.68(dd, J=9.8, 13.7Hz, 1H), 2.79(dd, J=5.6, 12.8Hz, 1H), 3.85(t, J=7.0Hz, 1H), 21

RS 111-115 3700-2400br, 3252, 1668, 1326, 1160 3.22-3.38(m, 2H), 4.17-4.24(m, 2H), 7.80(d, J=8.0Hz, 2H), 7.96(d, J=6.4 Hz, 2H) 22

RS — 3455, 3362, 1672, 1398, 1162 3.86(d, J=3.6Hz, 1H), 4.91 (d, J=3.6Hz, 1H) 23

R 196-197 3404, 3315, 1669, 1594, 1316, 1162 4.88(d, J=9.4Hz, 1H), 8.74(d, J=9.4Hz, 1H), 8.98(s, 1H), 10.92(s, 1H) 24

R 197-199 3700-2400(br), 3473, 1675, 1310, 1152 2.69(dd, J=7.6, 13.5Hz, 1H), 2.93(dd, J=7.6, 13.5Hz, 1H), 3.77(t, J=7.6Hz, 1H), (CD₃OD) 25

R 201-202 3700-2200(br), 3278, 1706, 1645, 1322, 1162 2.74(dd, J=8.3, 13.5Hz, 1H), 2.95(dd, J=6.5, 13.5Hz, 1H), 3.87(dd, J=6.5, 8.3Hz, 1H), (CD₃OD)

TABLE 4 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 26

R 63-65 3700-2200(br), 3362, 1670, 1590, 1336, 1152 2.60(dd, J=9.0, 13.8Hz, 1H), 2.79(dd, J=9.3, 13.8Hz, 1H), 3.76(m, 1H) 27

R 70-71 3700-2200br, 3372, 1674, 1531, 1348, 1310, 1161 2.66(dd, J=9.5, 13.6Hz, 1H), 2,79(dd, J=5. 4, 13.6Hz, 1H), 3.84(m, 1H), 7.73(A₂B₂qJ= 8.9Hz, 2H), 8.20(A₂B₂q, J=8.9Hz, 2H), 8.7 2(d, J=9.0Hz, 1H), 8.86(s, 1H), 10.7(s, 1H) 28 HOOC—CH₂—

R — — — 29 HOOC—CH₂—CH₂—

R — — — 30 HOCH₂—

R 192-193 3700-2400(br), 3392, 1667, 1320, 1161 3.29(dd, J=5.7, 10,7Hz, 1H), 3.43(dd, J= 8.4, 10.7Hz, 1H), 3.62(m, 1H), 7.85(A₂B ₂q, J=8.7Hz, 2H), 7.88(A₂B₂q, J=8.7Hz, 2H), 7.98(d, J=7.8Hz, 1H), 10.61(s, 1H) 31

R 69-70 3700-2200(br), 1671, 1329, 1163 2.69(dd, J=7.6, 13.5Hz, 1H), 2.93(dd, J=7.6, 13.5Hz, 1H), 3.77(t, J=7.6Hz, 1H), (CD₃OD) 32

R — — — 33

R 160-162 3401, 3260, 1673, 1316, 1165 2.66(dd, J=7.5, 13.4Hz, 1H), 2.96(dd, J=7.6, 14.2Hz, 1H), 3.81(m, 1H)

TABLE 5 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 34

R — — — 35

RS 141-145 3700-2400(br), 1672, 1443, 1327, 1094 2.84-3.21(m 2H), 4.29(m, 1H)

TABLE 6 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 2

RS 159-161 3276, 2503br, 1897br, 1724, 1344, 1170(Nujol) 2.95(dd, J=9.0, 14.0Hz, 1H), 3.12(dd, J=5.4, 14.0Hz, 1H), 4.13(m, 1H) , 7.29 (d, J=2.0Hz, 1H), 8.34(d, J=8.6Hz, 1H ), 8.88(d, J=2.0Hz, 1H), 12.79(br, 1H) 3

R 227-229 3386, 3305, 1747, 1363, 1323, 1161, 1135(Nujol) 2.88(dd, J=8.0, 14.0Hz, 1H), 3.09(dd, J=6.0, 14.0Hz, 1H), 3.91(m, 1H), 8.23 (m, 1H), 10.79(s, 1H), 12.70(br, 1H) 4

RS 181-189 2400-3700(br), 1734, 1484, 1327, 1160 2.75-3.06(m, 2H), 3.69(s, 3H), 3.90 (m, 1H) 5

RS 198-200 3446, 3065, 1594, 1397, 1303, 1154, 1094 3.17(dd, J=7.4, 13.8Hz, 1H), 3.57(dd, J=5.5, 13.9Hz, 1H) , 3.80(t, J=5.6Hz, 1H), 8.11(d, J=7.4Hz, 1H) 6

R 213-215 3184, 1723, 1337, 1317, 1156 2.77(dd, J=9.7, 13.7Hz, 1H), 3.03(dd, J=4.9, 13.3Hz, 1H), 3.93(m, 1H), 8.38 (d, J=8.8Hz, 1H) 7 CF₃CH₂—

R 176-177 3276, 1706, 1344, 1260, 1165 2.40-2.90(m, 2H), 4.05(m, 1H), 8.51 (d, J=9.0Hz, 1H), 13.2(br, 1H) 8

RS 153-156 3289, 1739, 1326, 1159, 1089 1.83(m, 2H), 2.52(m, 2H), 3.70(m, 1H), 8.32(d, J=9.0Hz, 1H) 11

R 103-105 2200-3700br, 3439, 3288, 1725, 1329, 1143 2.86(m, 1H), 2.87(s, 6H), 2.98(dd, J= 5.1, 13.8Hz, 1H), 4.15(m, 1H), 5.54 (m, 1H)

TABLE 7 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 13

RS 212-213 3113, 1724, 1520, 1345, 1158 2.86(dd, J=10.2, 13.2Hz, 1H), 3.14(dd, J=4.5, 13.7Hz, 1H), 4.02(m, 1H), 8.42(d, J=8.4Hz, 1H) 14

RS 164-165 3426, 3114, 1715, 1509, 1224, 1159 2.71(dd, J=9.9, 13.7Hz, 1H), 2.96(dd, J=5.3, 13.5Hz, 1H), 3.89(m, 1H), 8.34(d, J=9.0Hz, 1H) 15

R 85-87 2919, 1688, 1448, 1335, 1326, 1169 0.52-1.72(m, 13H), 3.68(m, 1H), 8.20(br.s, 1H) 16

RS 179-183 3432, 3294, 1713, 1482, 1341, 1159 2.80-3.12(m, 2H), 3.61(s, 3H), 3.94(m, 1H), 8.30(d, J=8,6Hz, 1H) 17

RS 115-120 3419, 3397, 3291, 1736, 1482, 1336, 1321, 1165 2.28(s, 3H), 2.78-3.10(m, 2H), 3.91 (m, 1H), 8.29(d, J=8.3Hz, 1H) 18

RS 208-211 3407, 3285, 1751, 1735, 1703, 1486, 1321, 1162 2.80-3.10(m, 2H), 3.92(m, 1H), 8.29(d, J=8.2Hz, 1H) 20

RS 197-205 2600-3700br, 1635, 1594, 1335, 1163, 1095 2.60-3.04(m, 2H), 3.98(m, 1H) 21

RS 196-199 2200-2700br, 1713br, 1345, 1125 3.24-3.56(m, 2H), 4,34(m, 1H)

TABLE 8 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 22

RS 141-143 3335, 3246, 1732, 1315, 1152 4.10(d, J=3.2Hz, 1H), 5.13(d, J= 3.2Hz, 1H) 23

R 211-214 3316, 1734, 1325, 1159(Nujol) 4.94(d, J=9.4Hz, 1H), 8.80(d, J= 9.4Hz,1H), 13.0(br.s, 1H) 28 HOOC—CH₂—

R 171-173 3353, 1752, 1326, 1155, 1096 2.45(dd, J=6.2, 16.4Hz, 1H)2.63(dd, J=6.6, 16.4Hz, 1H), 29 HOOC—CH₂—CH₂—

R 185-187 3270, 1709, 1336, 1159, 1093 1.68(dd, J=7.9, 14.1Hz, 1H), 1.87(dd, J=6.0, 13.4Hz, 1H), 2.22(t, J=7.2Hz, 2H), 3.80(m, 1H), 30 HOCH₂—

R 277-279 2200-3700br, 3430, 3292, 1728, 1324, 1162 3.51(dd, J=6.0, 12.9Hz, 1H), 3.55(dd, J=5.4, 12.9Hz, 1H), 3.80(m, 1H), 8.06(d, J=8.7Hz, 1H) 31

R 89-91 2200-3700br, 3432, 3289, 1733, 1330, 1165 3.54(dd, J=4.8, 9.9Hz, 1H), 3.60(dd, J=5.7, 9.9Hz, 1H), 4.04(m, 1H), 4.39(s, 2H), 8.34(d, J=8,1Hz, 1H) 32

R >270 3319, 3052, 1701, 1317, 1284, 1162 2.81(dd, J =9.7, 13.7Hz, 1H), 3.05(dd, J=4.8, 13.4Hz, 1H), 3.96(m, 1H), 8.40(d, J=9.0Hz, 1H), 12.88(br.s, 1H)

TABLE 9 (Ia)

Example mp (decomp.) No. R¹ R¹⁸ * (° C.) 34

R 243-246 35

RS 151-156 Example IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (KBr) d₆-DMSO 34 3420, 1588, 1402, 3.06(dd, J=5.4, 14.4Hz, 1H), 3.14(dd, 1324, 1151 J=5.1, 14.4Hz, 1H), 3.65(t, J=5.4Hz, 1H), 6.92(m, 1H), 10.72(s, 1H) 35 2200-3700br, 1734, 3.17-3.50(m, 2H), 4.51(m, 1H) 1334, 1161

TABLE 10 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 36

RS >145 1726, 1354 1326, 1161 — 37

RS — 1732, 1594 1404, 1155 — 38

R 188-190 1607, 1594 1294, 1153 C₂₄H₂₂N₂O₅S.0.5H₂O Calc. C:62.73 H:5.04 N:6.10 S:6.98 Foun. C:62.75 H:5.06 N:6.31 S:7.05 39

R 90-93 1724, 1594 1326, 1159 C₂₄H₂₂N₂O₅S.0.8H₂O Calc. C:62.00 H:5.12 N:6.03 S:6.90 Foun. C:62.03 H:5.06 N:6.08 S:6.82 40

R 149-152 1685, 1349 1166 — 41

R 104-107 1725, 1599 1372, 1173 — 42

R 167-169 1745, 1653 1391, 1147 — 43 (CH₃)₂CH—

R 155-157 1714, 1594 1334, 1166 C₁₇H₁₉NO₄S0.1CF₃COOH Calc. C:59.99 H:5.58 N:4.06 S: 9.30 Foun. C: 60.37 H:5.74 N:4.13 S: 9.76

TABLE 11 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 44 (CH₃)₂CH—

R 196-197 1724, 1340 1328, 1167 C₂₁H₂₇NO₄S.0.3H₂O Calc. C:63.87 H:7.04 N:3.55 S:8.12 Foun. C:63.84 H:6.86 N:3.42 S:8.01 45 (CH₃)₂CH—

R 241-243 1734, 1719 1324, 1160 C₂₃H₂₃NO₄S.0.3H₂O Calc. C:66.58 H:5.73 N:3.38 S:7.73 Foun. C:66.45 H:5.52 N: 3.24 S:7.56 46 (CH₃)₂CH—

R 157-159 1670, 1375 1148 — 47 (CH₃)₂CH—

R 175-176 1717, 1694 1349, 1165 — 48 (CH₃)₂CH—

R 145-147 1634, 1334 1158 C₁₇H₁₈FNO₄S Calc. C:58.11 H:5.16 F:5.41 N:3.99 S:9.12 Foun. C:58.11 H:5.17 F:5.86 N:3.92 S:9.69 49 (CH₃)₂CH—

R 183-186 1681, 1319 1162 — 50

R 183-184 1725, 1340 1159 — 51

R 224-226 1750, 1324 1159 C₂₇H₂₃NO₄S.0.7H₂O Calc. C:68.98 H:5.23 N:2.98 S:6.82 Foun. C:69.08 H:5.09 N:2.91 S:6.73

TABLE 12 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 52

R 157-160 1685, 1349 1166 — 53

R 111-112 1691, 1567 1390, 1159 — 54

R 194-195 1749, 1592 1323, 1164 — 55 (CH₃)₂CH—

R 197-199 1746, 1337 1164 C₁₈H₂₁NO₄S₂.0.2H₂O Calc. C:56.43 H:5.63 N:3.66 S:16.74 Foun. C:56.74 H:5.67 N:3.86 S:16.35 56

R 108-110 1649, 1337 1165 — 57

R 187-190 1588, 1308 1141 — 58

R 239-243 1744, 1592 1323, 1160 C₂₁H₁₈N₂O₄S₂.0.3H₂O Calc. C:58.40 H:4.34 N:6.45 S:14.85 Foun. C:58.40 H:4.44 N:6.58 S:14.57 59

R 222-224 1751, 1734 1537, 1347 1172 C₁₇H₁₄ClN₃O₆S.0.3H₂O Calc. C:47.48 H:3.44 Cl:8.39 N:9.65 S:7.52 Foun. C:47.57 H:3.43 Cl:8.26 N:9.79 S:747

TABLE 13 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 60

R foam 3700-2400br, 3277, 1669, 1325, 1152 2.60(dd, J=8.7, 13.7Hz, 1H), 2.79(dd, J=6.0, 13.7Hz, 1H), 3.75(ddd, J=6.0, 8.7, 9.0, 1H), 6.94(d, J=8.9Hz, 2H) 61

R 115-118 3302, 1667, 1324, 1153(Nujol) 2.71(dd, J=7.0, 14.4Hz, 1H), 2.96(dd, J=7.0, 14.2Hz, 1H), 3.78(t, J=7.6Hz, 1H) 62

S — 3406, 1670, 1582, 1325, 1153 2.71(dd, J=7.9, 14.4Hz, 1H), 2.96(dd, J=7.6, 14.4Hz, 1H), 3.78(dd, J=7.2, 7.3Hz, 1H) 63 (CH₃)₂CH—

R 149-151 3268, 1634, 1584, 1336, 1157 0.76(d, 6.6Hz, 6H), 1.77(m, 1H), 3.26(m, 1H) 64

RS — 3314, 1669, 1582, 1420, 1328, 1154 2.71(dd, J=7.9, 14.2Hz, 1H), 2.93(dd, J=6.5, 14.3Hz, 1H), 3.65(s, 3H), 3.78 (dd, J=7.1, 7.2Hz, 1H) 65

RS — 3405, 1671, 1582, 1487, 1324, 1154 2.34(s, 3H), 2.65(dd, J=7.8, 14.1Hz, 1H), 2.93(dd, J=7.6, 14.4Hz, 1H), 3.75(dd, J=6.8, 7.7Hz, 1H) 66

RS — 3317, 1670, 1582, 1488, 1323, 1153 2.71(dd, J=8.9, 14.4Hz, 1H), 2.89(dd, J=6.6, 14.4Hz, 1H), 3.75(dd, J=6.5, 6.8Hz, 1H) 67

RS — 3421, 1702, 1676, 1582, 1354, 1328, 1153 2.54(s, 3H), 2.69-2.89(m, 2H), 3.87 (m, 1H)

TABLE 14 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 60

R 108-109 2400-3600br, 3345, 3213, 1735, 1700, 1346, 1163 2.72(dd, J=8.7, 13.6Hz, 1H), 2.94(dd, J=5.6, 13.6Hz, 1H), 3.84(ddd, J=5.6, 8.7, 8.7Hz, 1H), 8.23(d, J=8.7Hz, 1H) 61

R 82-87 3410, 3276, 1724, 1582, 1488, 1331, 1152(Nujol) 2.88(dd, J=7.4, 15.2Hz, 1H), 3.07(dd, J=6.2, 14.4Hz, 1H), 3.83(m, 1H), 8.08 (m, 1H), 10.80(s, 1H), 12.70(br, 1H) 62

S foam 3412, 1724, 1582, 1488, 1332, 1152 2.81-3.12(m, 2H), 3.88(m, 1H), 8.19 (d, J=8.4Hz, 1H) 63 (CH₃)₂CH—

R 137-138 3154, 1720, 1688, 1583, 1488, 1251 0.89(d, J=7.0Hz, 3H), 0.98(d, J=6.8 Hz, 3H), 2.12(m, 2H), 3.80(dd, J=4.7 , 9.7Hz, 1H), 5.17(d, J=9.6Hz, 1H) 64

RS — 3273, 1724, 1582, 1487, 1331, 1198, 1153 2.78-3.10(m, 2H), 3.67(s, 3H), 3.86(m, 1H) 65

RS — 3409, 3281, 1725, 1582, 1331, 1197, 1153 2.34(s, 3H), 2.75-3.08(m, 2H), 3.86(m, 1H), 8.19(d, J=8.4Hz, 1H) 66

RS — 3415, 1725, 1582, 1488, 1329, 1196, 1174, 1152 2.78-3.08(m, 2H), 3.85(m, 1H), 8.18 (d, J=8.6Hz, 1H) 67

RS 236-237 3296, 1742, 1647, 1604, 1581, 1342, 1334, 1152 2.55(s, 3H), 2.79-3.11(m, 2H), 3.98 (m, 1H)

TABLE 15 (Ia)

Example No. R¹ R¹⁸ * 68

R 69

RS 70

RS Example mp (decomp.) IR (ν cm⁻¹) No. (° C.) (KBr) Elemental anaylsis 68 >240 1608, 1590 — 1507, 1232 1157 69 — 1735, 1583, C₂₄H₂₂N₂O₇S₂ 1362, 1171 Calc. C:56.02 H:4.31 N:5.44 S:12.46 Foun. C:55.75 H:4.40 N:5.41 S:12.21 70 — 1733, 1583 — 1150

TABLE 16 (Ib)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 71

R 129-131 3700-2400br, 3247, 1636, 1337, 1160 0.90(t, J=6.8Hz, 3H), 1.22-1.40(m, 4H), 1.52-1.6 7(m, 2H), 2.62(t, J=7.7Hz, 2H), 2.86(dd, J=8.4, 4.13 .7Hz, 1H), 3.02(dd, J=5.7, 13.7Hz, 1H)(CDCl₃) 72

CH₃(CH₂)₇— R oil 3700-2400br, 1663, 1320, 1145(film) 0.87(t, J=6.3Hz, 3H), 2.50(t, J=7.4Hz, 2H), 2.76(dd, J=9.6, 14.0Hz, 1H), 2.87(dd, J=5. 8, 14.0Hz, 1H), 3.84(dd, J=5.8, 9.6Hz, 1H), 73

CH₃(CH₂)₃— R oil 3600-2400br, 3262, 1673, 1321, 1142(CHCl₃) 0.79(t, J=7.0Hz, 3H), 2.32-2.56(m, 2H), 2.92(m, 1H), 3.26(m, 1H), 74

R — — — 75

R 85-86 3700-2200(br), 3262, 1639, 1332, 1156 2.80(m, 1H), 2.96(m, 1H), 3.94(s, 2H), 3.86( m, 1H), 6.80-7.52(m, 10H), 7.08(A₂B₂qJ=7. 5Hz, 2H), 7.42(A₂B₂q, J=7.5Hz, 2H)(CDCl₃) 76

R — — —

TABLE 17 (Ib)

Example mp (decomp.) No. R¹ R¹⁸ * (° C.) 77

R 138-139 78

R 69-70 79

R — Example IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (KBr) d₆-DMSO 77 3700-2400(br), 3312, 2.79(dd, J=8.5, 13.4Hz, 1H), 2.89(dd, 1629, 1329, 1144 J=6.0, 13.4Hz, 1H), 3.81(dd, J=6.0, 8.5Hz, 1H), 6.55(d, J=15.5Hz, 1H) 78 3700-2200(br), 1670, 2.78(dd, J=8.6, 13.4Hz, 1H), 2.91(dd, J= 1318, 1152 6.0, 13.4Hz, 1H), 3.92(ABq, J=13.5Hz, 1H), 3.90(m, 1H), 9.01(s, 1H), 10.78(s, 1H) 79 — —

TABLE 18 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ * (° C.) (KBr) d₆-DMSO 71

R 121-122 2300-3700br, 3426, 3318, 1713, 1330, 1159 0.89(t, J=6.7Hz, 3H), 2.62(t, J=7.6Hz, 2H), 2.96(d d, J=7.0, 13.9Hz, 1H), 3.10(dd, J=5.4, 4.13, 9Hz, 1H) , 4.19(dt, J=6.9, 8,2Hz, 1H), 5.30(d, J=8,2Hz, 1H), 72

CH₃(CH₂)₇— R oil 2400-3600br, 3340, 1736, 1334, 1142(CHCl₃) 0.88(t, J=6.9Hz, 3H), 2.55-2.73(m, 2H), 2.9 7(dd, J=8.4, 13.8Hz, 1H), 3.24(dd, J=4.8, 13. 8Hz, 1H), 4.35(m, 1H), 4.98(m, 1H), (CDCl₃) 73

CH₃(CH₂)₃— R 89-90 2300-3700br, 3240, 1725, 1341, 1144 0.84(t, J=7.1Hz, 3H), 2.57-2.70(m, 2H), 2.97(d d, J=8.4, 13.9Hz, 1H), 3.25(dd, J=4.8, 13.9Hz, 1 H), 4.35(m, 1H), 4.96(d, J=9.6Hz, 1H)(CDCl₃) 74

R >250 3421, 1580, 1333, 1421, 1153 2.41(s, 3H), 3.01(dd, J=6.0, 14.4Hz, 1H), 3. 12(dd, J=4.5, 14.4Hz, 1H), 3.67(t, J=5.4Hz, 1H), 6.79(m, 1H), 6.89(m, 1H), 10.59(s, 1H) 76

R foam 3413, 1594, 1456, 1416, 1157 3.03(dd, J=6.5, 15.1Hz, 1H), 3.15 (dd, J=4.7, 14.1Hz, 1H), 3.64(t, J=5.1Hz, 1H), 10.68(s, 1H) 77

R — 2400-3700br, 3252, 1765, 1725, 1301, 1140 2.81(dd, J=9.2, 13.7Hz, 1H), 3.03(dd, J=5.4, 13.7H z, 1H), 3.94(dt, J=5.4, 9.2Hz, 1H), 6.66(d, J=15.2H z, 1H), 7.16(d, J=15.2Hz, 1H), 8.01(d, J=9.2Hz, 1H) 78

R — 2200-3700br, 3268, 1726, 1321, 1152(film) 2.81(dd, J=9.2, 13.7Hz, 1H), 3.00(dd, J =5.6, 13.7Hz, 1H), 4.01(ABq, J=13.7Hz , 2H), 4.01(m, 1H), 7.65(d, J=8.3Hz, 1H) 79

R — 3413, 2931, 1720, 1585, 1455, 1421, 1313, 1144 0.90-1.68(m, 9H), 1.78(m, 1H), 2.74 (m, 1H), 3.00-3.20(m, 2H), 3.77(m, 1H)6.45(br.s, 1H), 6.77(br.s, 1H)

TABLE 19 (Ia)

Exam- mp ple (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 80

R 153-155 1704, 1596 1349, 1164 — 81

n-C₈H₁₇— R >130 1576, 1356 1139 — 82

R 128-130 1732, 1342 1167 C₂₄H₁₉N₃O₅S.1.3H₂O Calc. C:59.45 H:4.49 N:8.67 S:6.61 Foun. C:59.43 H:4.45 N:8.59 S:6.58 83

R 210-214 1745, 1590 1316, 1157 — 84

R 198-200 1594, 1456 1200, 1188 —

TABLE 20 (Ib)

Example mp (decomp.) No. R¹ R¹⁸ * (° C.) 85

R 157-160 86

R 138-142 87

S 206-207 Example IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (KBr) d₆-DMSO 85 3700-2400br, 3273, 2.65(dd, J=8.9, 13.6Hz, 1H), 2.82(dd, 1633, 1338, 1166 J=6.6, 13.6Hz, 1H), 3.86(m, 1H), 7.75 (d, J=7.8Hz, 2H), 7.87(d, J=8.7Hz, 2H) 86 3700-2400br, 2921, 2.62(dd, J=8.6, 13.5Hz, 1H), 2.81(dd, J= 1672, 1314, 1165, 6.5, 13.6Hz, 1H), 3.09(s, 6H), 3.83(m, 1H), 6.86(d, J=9.0Hz, 2H), 7.83(d, J=8.8Hz, 2H) 87 3700-2400(br), 3357, 1686, 2.57(dd, J=8.3, 13.6Hz, 1H), 2.79(dd, J=6.0, 13.6Hz, 1 1641, 1314, 1155 H), 3.76(m,1 H), 8.02(d, J=8.7Hz, 1H), 8.80(s, 1H), 8.85 (d, J=1.7Hz, 1H), 9.06(s, 1H), 10.59(d, J=1.7Hz, 1H)

TABLE 21 (Ia)

Example mp (decomp.) No. R¹ R¹⁸ * (° C.) 85

R 172-174 86

R 93-94 87

S 203-204 Example IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (KBr) d₆-DMSO 85 2400-3600br, 3426, 3296, 2.75(dd, J=9.1, 13.7Hz, 1H), 2.98(dd, 1698, 1350, 1167 J=5.5, 13.7Hz, 1H), 3.96(ddd, J=5.5, 9.1, 9.1Hz, 1H), 8.51(d, J+9.1Hz, 1H) 86 2200-3700br, 3431, 2.74(dd, J=9.1, 13.6Hz, 1H), 2.96(dd, J= 1735, 1391, 1154 5.7, 13.6Hz, 1H), 3.09(s, 6H), 3.93(dt, J=5.7, 9.1Hz, 1H), 8.39(d, J=9.1Hz, 1H) 87 2300-3700br, 3358, 2.71(dd, J=9.1, 13.7Hz, 1H), 2.93(dd, J=5.6, 3262, 1718, 1686, 13.7Hz, 1H), 3.84(dt, J=5.6, 9.1Hz, 1H), 8.11 1660, 1313, 1159 (d, J=9.1Hz, 1H), 8.78(s, 1H), 9.06(s, 1H)

TABLE 22 (Ia)

Example No. R¹ R¹⁸ * 88

R 89 (CH₃)₂CH—

R 90 (CH₃)₂CH—

R 91

R Example mp (decomp.) IR (ν cm⁻¹) No. (° C.) (KBr) Elemental anaylsis 88 103-106 1719, 1390 — 1229 89 96-99 1734, 1461 C₁₇H₂₀N₂O₆S₂.0.9Ethylether 1327, 1158 Calc. C:51.63 H:6.10 N:5.85 S:13.38 Foun. C:51.23 H:6.17 N:5.87 S: 13.11 90 110-112 1724, 1325 C₁₈H₂₁N₃O₆S₂.0.8Ethylether 1168 Calc. C:51.05 H:5.86 N:8.42 S:12.86 Foun. C:50.75 H:5.89 N:8.15 S:12.47 91  98-101 1735, 1598 C₂₁H₁₉BrN₂O₆S₂.0.5CF₃COOH 1327, 1185 Calc. C:44.30 H:3.30 Br:13.40 N:4.70 S:10.75 Foun. C:44.62 H:3.52 Br:13.07 N:4.64 S:10.85

EXAMPLE 92

(Method B)

Process 1

To a solution of D-valine methylester hydrochloride (XV-2) (755 mg, 4.5 mmol) in dichloromethane(12 ml) was added N-methylmorpholine (1.49 ml, 3×4.5 mmol) and 5-bromo-2-thiophensulfonyl chloride (1.24 g, 1.05×4.5 mmol) was added under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCl, 5% NaHCO₃, and water. The organic layer was concentrated in vacuo, and dried over Na₂SO₄. The residue was subjected to silica gel column chromatography and the fractions eluting with ethyl acetate/hexane=⅓ were collected and washed with n-hexane to give 1.32 g of the desired compound (XVII-1).

Yield 82%. mp. 109-1110° C.

Elemental analysis C₁₀H₁₄BrNO₄S₂ Calcd. : C; 33.71 H; 3.96 Br; 22.43 N; 3.93 S;1 8.00 Found: C; 33.75 H; 3.89 Br; 22.43 N; 3.96 S; 17.86

[α]_(D): −34.5±0.7(c=1.012 CHCl₃ 25° C.)

IR(CHCl₃, υ max cm⁻¹) 1737,1356,1164,1138

NMR (CDCl₃, δ ppm): 0.89(d, J=6.8 Hz, 3H), 1.00(d, J=6.8 Hz, 3H), 2.00 (m, 1H), 3.60(s, 3H), 3.83(dd, J=5.2, 10.0 Hz, 1H), 5.20(d, J=10.0 Hz, 1H), 7.04(d, J=4.1 Hz, 1H), 7.32(d, J=4.1 Hz, 1H)

Process 2

To a degassed solution of 400 mg (1.12 mmol) of compound (XVII-1) in 5 ml of dimethylformamide was added 222 mg (1.5×1.12 mmol) of 4-methoxyphenylacetylene and 21 mg(0.1×1.12 mmol) of copper iodide (I) under an argon atmosphere. Then 39 mg (0.05×1.12 mmol) of bis(triphenylphosphine)palladium dichloride (II) and 0.47 ml (3×1.12 mmol) of triethylamine were added to the reaction mixture. The resulting mixture was degassed and stirred overnight under an argon atmosphere at 50° C. The reaction mixture was diluted with ethyl acetate. The organic later was washed with 1N HCl, 5 % NaHCO₃, and water, dried over Na₂SO₄, and concentrated in vacuo. The resulting residue was column chromatographed on silica gel. The fractions eluting with n-hexane/ethyl acetate=2/1 were collected and recrystallized from ethyl acetate/n-hexane to give 392 mg of the desired compound (XVIII-1).

Yield 86 %. mp. 131-132° C.

Elemental analysis C₁₉H₂NO₅S₂.0.2 H₂O Calcd. : C; 55.51 H; 5.25 N; 3.41 S; 15.60 Found: C; 55.80 H; 5.19 N; 3.38 S; 15.36

IR(KBr, υ max cm⁻¹) : 3268,2203,1736,1604,1524,1348,1164.

NMR(CDCl₃, δ ppm): 0.90(d, J=6.6 Hz, 3H), 1.00(d, J=7.0 Hz, 3H), 2.00(m, 1H), 3.60(s, 3H), 3.84(s, 3H), 3.86(dd, J=5.0, 10.2 Hz, 1H), 5.21(d, J=10.2 Hz, 1H), 6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).

Process 3

To a solution of 407 mg (1 mmol) of compound (XVII-1) in 8 ml of tetrahydrofuran and 8 ml of methanol was added 5.1 ml of 1N NaOH. The resulting mixture was stirred for 6 h at 60° C. The reaction mixture was concentrated in vacuo to remove an organic solvent, and the residue was diluted with ethyl acetate. The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give 373 mg of compound (Ia-2-1).

Yield 100%. mp. 147-148° C.

IR (KBr, υ max cm⁻¹): 1710,1604,1351,1216.

Elemental analysis C₁₈H₁₉NO₅S₂. 0.2H₂O Calcd.: C; 54.45 H; 4.92 N; 3.53 S; 16.15 Found: C; 54.39 H; 4.93 N; 3.79 S; 15.96

EXAMPLE 93-156

The compounds which were shown in Tables 23 to 30 were synthesized in a manner similar to those described in Example 92.

TABLE 23 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 93

R 165-170 1590, 1316 1137 — 94

R 223-226 1747, 1323 1134 C₂₆H₂₂N₂O₅S Calc. C:65.81 H:4.67 N:5.90 S:6.76 Foun. C:65.34 H:4.90 N:5.56 S:6.40 95

R 216-218 1724, 1325 1135 — 96

R 111-114 1739, 1336 1163 — 97

R 178-180 1710, 1511 1329, 1161 — 98

R 105-108 1725, 1618 1373, 1163 — 99

R >250 1706, 1606 1350, 1164 C₂₆H₂₀N₂O₆S.0.4H₂O Calc. C:63.00 H:4.23 N:5.65 S:6.47 Foun. C:62.99 H:4.32 N:5.82 S:6.76 100

R 176-177 1735, 1633 1321, 1173 C₂₅H₂₁N₃O₄S.0.8H₂O Calc. C:63.36 H:4.81 N:8.87 S:6.77 Foun. C:63.45 H:4.92 N:8.77 S:6.57

TABLE 24 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 101

R 227-229 1736, 1618 1398, 1168 C₂₆H₂₂N₂O₄S.0.2H₂O Calc. C:67.57 H:4.89 N:6.06 S:6.94 Foun. C:67.66 H:4.77 N:6.09 S:6.71 102

R 230-233 1735, 1654 1399, 1164 — 103

R 234-236 1732, 1631 1372, 1148 — 104

R >200 decomp. 1600, 1558 1336, 1171 105 (CH₃)₂CH—

R 146-149 1795, 1718 1331, 1168 — 106 (CH₃)₂CH—

R 231-232 1719, 1595 1344, 1167 C₁₉H₁₈N₂O₆S.0.1H₂O Calc. C:56.46 H:4.54 N:6.93 S:7.93 Foun. C:56.30 H:4.37 N:7.14 S:7.85 107 (CH₃)₂CH—

R 166-169 1728, 1631 1372, 1148 — 108 (CH₃)₂CH—

R 163-165 1728, 1332 1172 —

TABLE 25 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 109 (CH₃)₂CH—

R 187-189 1720, 1656 1319, 1165 — 110 (CH₃)₂CH—

R 111-114 1724, 1635 1366, 1158 — 111 (CH₃)₃C—

R 161-162 1711, 1683 1600, 1328 1159 C₂₁H₂₃NO₅S.1.3H₂O Calc. C:59.36 H:6.07 N:3.30 S:7.55 Foun. C:59.36 H:6.06 N:3.50 S:7.44 112 CH₃CH₂(CH₃)CH—

R 157-159 1732, 1680 1329, 1167 — 113

R 133-136 1735. 1651 1348, 1165 — 114

R 183-185 1727, 1604 1335, 1182 — 115

R 166-168 1725, 1663 1399, 1197 C₂₃H₁₈FNO₄S.0.3H₂O Calc. C:64.41 H:4.37 F:4.43 N:3.27 S:7.48 Foun. C:64.37 H:4.38 F:4.96 N:3.31 S:7.24 116 (CH₃)₂CH—

R 163-165 1728, 1332 1172 —

TABLE 26 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 117 (CH₃)₂CH—

R 187-189 1720, 1656 1319, 1165 — 118

R 111-114 1724, 1635 1366, 1158 — 119

R 167-169 1585, 1318 1153 — 120

R — 1605, 1523 1340, 1151 — 121

R — 1604, 1524 1336, 1173 — 122

R 103-106 1721. 1620 1339, 1163 — 123

R 180-182 1729, 1675 1340, 1168 — 124 (CH₃)₂CH—

R 147-148 1710, 1604 1351, 1216 C₁₈H₁₉NO₅S₂.0.2H₂O Cacl. C:54.45 H:4.92 N:3.53 S:16.15 Foun. C:54.39 H:4.93 N:3.79 S:15.96

TABLE 27 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 125 (CH₃)₂CH—

R 157-158 1712, 1350 1163 C₁₈H₁₉NO₄S₂.0.2H₂O Calc. C:56.73 H:5.13 N:3.68 S:16.83 Foun. C:57.03 H:5.30 N:3.89 S:16.56 126 (CH₃)₂CH—

R 154-156 1710. 1499 1356, 1165 — 127

R 149-150 1695, 1334 1184 C₂₂H₁₉NO₅S₂.0.2H₂O Calc. C:59.36 H:4.39 N:3.15 S:14.41 Foun. C:59.43 H:4.61 N:3.25 S:14.02 128

R 161-164 1710, 1329 1180 — 129

R 155-158 1734, 1699 1324, 1105 C₂₁H₁₆FNO₄S₂ Calc. C:58.73 H:3.75 F:4.42 N:3.26 S:14.93 Foun. C:58.66 H:3.93 F:4.52 N:3.33 S:14.41 130

R — — — 131

R — — — 132

R — — —

TABLE 28 (Ia)

Exam- ple mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 133

R — — — 134

R — — — 135

R — — — 136

R — — — 137

R — — — 138

R — — — 139

R — — — 140

R — — —

TABLE 29 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) Elemental No. R¹ R¹⁸ * (° C.) (KBr) anaylsis 141

R — — — 142

R — — — 143

R — — — 144

R — — — 145

R — — — 146

R — — — 147

R — — — 148

R — — —

TABLE 30 (Ia)

Exam- ple mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 149

R — — — 150

R — — — 151

R — — — 152

R — — — 153

R — — — 154

R — — — 155

R — — — 156

R — — —

EXAMPLE 157, 158

Process 1 (R²=CH₃)

To a solution of 150 mg (0.33 mmol) of compound (XVIII-2) in 2 ml of dimethylformamide which was synthesized the same manner as those described in Example 96 was added 227 mg (5×0.33 mmol) of potassium carbonate and 0.1 ml (5×0.33 mmol) of methyl iodide, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over Na₂SO₄, and concentrated in vacuo to give 373 mg of N-methyl derivative as an oil.

Yield 91%.

Elemental analysis C₂₄H₂₃NO₅S₂ Calcd. : C; 61.39 H; 4.94 N; 2.98 S; 13.66 Found: C; 61.22 H; 5.18 N; 2.93 S; 13.27

Further, a solution of 140 mg of the above oily compound which was obtained the above process in 2 ml of methanol was added 0.6 ml of 1N NaOH, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed with water, dried over Na₂SO₄, and concentrated in vacuo to give 105 mg of compound (Ia-2-66) (R=Me).

Yield 77%. mp. 185-186° C.

Elemental analysis C₂₃H₂₁NO₅S Calcd. : C; 60.64 H; 4.65 N; 3.07 S; 14.08 Found: C; 60.56 H; 4.84 N; 3.01 S; 13.94.

IR (KBr, υ max cm⁻¹) : 3600-2300 br, 3426, 2203, 1710, 1604, 1503, 1344, 1151. NMR (d₆-DMSO, δ ppm): 2.88(s, 3H), 2.93(dd, J=12.0, 10.2 Hz, 1H), 3.19 (dd, J=14.2, 5.6 Hz, 1H), 3.81(s, 3H), 4.74(dd, J=5.4, 10.2 Hz, 1H), 6.99-7.04(m, 2H), 7.20-7.35(m, 7H), 7.52-7.56(m, 2H), 6.90(d, J=9.0 Hz, 2H), 7.44(d, J=9.0 Hz, 2H), 7.12(d, J=4.0 Hz, 1H), 7.44(d, J=4.0 Hz, 1H).

The compound Ia-2-67) (R²=CH₂Ph) was synthesized in the same manner as those described in Example 157.

IR(KBr, υ max cm⁻¹): 2200,1722,1340,1151.

NMR (d₆-DMSO, δ ppm) : 2.94(dd, J=7.6, 13.8 Hz, 1H), 3.19(dd, J=7.2, 14.4 Hz, 1H), 3.83(s, 3H), 4.29(d, J=16.2 Hz, 1H), 4.62(d, J=16.2 Hz, 1H) (Only characteristic peaks are shown.)

EXAMPLE 159

(Method C)

Process 1

To a solution of 500 mg (1.4 mmol) of compound(XVII-2) which was obtained Example 96 in 12 ml of dry tetrahydrofuran was added 387 mg (2×1.4 mmol) of powdery potassium carbonate, 319 mg (1.5×1.4 mmol) of 4-methoxyphenylboronic acid and 81 mg (0.05×1.4 mmol) of tetrakis(triphenylphosphine)palladium. The resulting mixture was stirred under argon atmosphere for 48 h at 75° C. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1N HCl, 5% NaHCO₃ aq., and water, dried over Na₂SO₄, and concentrated in vacuo. The residue was column chromatographed on silica gel. The fractions eluting with n-hexane/ethyl acetate=3/1 were collected and recrystallized from n-hexane to give 447 mg of the desired compound (XIX-1).

Yield 83 %. mp. 122-123° C.

Elemental analysis C₁₇H₂₁NO₅S₂ Calcd. : C; 53.25 H; 5.52 N; 3.65 S; 16.72 Found: C; 53.26 H; 5.50 N; 3.69 S; 16.63

[α]_(D)−21.7±0.6 (c=1.000 DMSO 25° C.)

IR (KBr, υ max cm⁻¹): 1735,1605,1505,1350,1167,1136

NMR (CDCl₃, δ ppm): 0.90(d, J=7.0 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 2.10(m, 1H), 3.54(s, 3H), 3.85(s, 3H), 3.87(dd, J=5.0, 10.2 Hz, 1H), 5.20(d, J=10.2 Hz, 1H), 6.94(d, J=9.0 Hz, 2H), 7.52(d, J=9.0 Hz, 2H), 7.11(d, J=4.0 Hz, 1H), 7.49(d, J=4.0 Hz, 1H).

Process 2

To a solution of 390 mg (1.01 mmol) of compound (XIX-1) in 8ml of tetrahydrofuran and 8ml of methanol was added 5.1 ml of 1N NaOH, and resulting mixture was stirred at 60° C. for 6 h. The reaction mixture was concentrated in vacuo to remove an organic solvent. The resulting residue was diluted with ethyl acetate. The mixture was acidified with aqueous solution of citric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated in vacuo to give 373 mg of compound (Ia-3-1).

Yield 100%. mp. : 174-176° C.

IR(KBr, υ max cm⁻¹): 1735, 1503, 1343, 1163.

EXAMPLE 160-175

The compounds which were shown in Tables 31 to 32 were synthesized in a manner similar to those described in Example 159,.

TABLE 31 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental anaylsis 160

R 93-96 1667, 1337 1180 — 161

R 157-159 1670, 1339 1194 — 162

R 168-171 1725, 1598 1371, 1185 — 163

R 226-230 1735, 1341 1159 C₂₂H₂₀N₂O₄S₃.0.4H₂O Calc. C:55.07 H:4.37 N:5.84 S:20.05 Foun. C:55.35 H:4.43 N:6.04 S:19.65 164 (CH₃)₂CH—

R 174-176 1735, 1503 1343, 1163 — 165 (CH₃)₂CH—

R 165-167 1713, 1353 1163 — 166 (CH₃)₂CH—

R 146-147 1792, 1504 1352, 1168 C₁₅H₁₆FNO₄S₂.0.1H₂O Calc. C:50.15 H:4.55 F:5.29 N:3.90 S:17.85 Foun. C:49.99 H:4.58 F:5.22 N:4.05 S:17.77 167 (CH₃)₂CH—

R 157-159 1747, 1324 1159 C₁₆H₁₉NO₄S₃ Calc. C:49.85 H:4.97 N:3.63 S:24.95 Foun. C:49.70 H:5.00 N:3.93 S:24.96

TABLE 32 (Ia)

Exam- mp ple (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 168

R 161-165 1735, 1698 1374, 1163 C₂₀H₁₉NO₅S₂ Calc. C:57.54 H:4.59 N:3.35 S:15.36 Foun. C:57.62 H:4.72 N:3.52 S:15.27 169

R 166-167 1713, 1609 1378, 1194 C₂₀H₁₉NO₄S₂ Calc. C:59.83 H:4.77 N:3.49 S:15.97 Foun.C:59.77 H:4.86 N:3.61 S:15.86 170

R 174-175 1721, 1654 1365, 1148 C₁₉H₁₆FNO₄S₂ Calc. C:56.28 H:3.98 F:4.09 N:3.45 S:15.82 Foun. C:56.33 H:4.09 F:4.65 N:3.65 S:15.84 171

R 203-205 1750, 1730 1428, 1325 1155 C₂₀H₁₉NO₄S₃.0.2H₂O Calc. C:54.95 H:4.47 N:3.20 S:22.00 Foun. C:55.05 H:4.52 N:3.34 S:22.04 172

R — — — 173

R — — — 174

R — — — 175

R — — —

EXAMPLE 176

(Method D)

Process 1

To a solution of 10 g (47.68 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 100 ml of dichloromethane was added 15.7 ml (3×47.68 mmol) of N-methylmorpholine and 14.1 g(1.2×47.68 mmol) of 4-nitrobenzenesulfonyl chloride under ice-cooling. After being stirred for 5 h at room temperature the reaction mixture was washed with 2N HCl, 5% NaHCO₃, water. The organic layer was dried over Na₂SO₄ and concentrated in vacuo, and the resulting residue was recrystallized from dichloromethane/n-hexane to give 13.3 g of the desired compound (XX-1).

Yield 77.8%. mp. 89-90° C.

Elemental analysis C₁₅H₂₂N₂O₆S Calcd. : C; 50.27 H; 6.19 N; 7.82 S; 8.95 Found: C; 50.04 H; 6.10 N; 7.89 S; 8.84

[α]_(D) −2.9±0.8(c=0.512 DMSO 23° C.)

IR(KBr, υ max cm⁻¹): 3430br, 3301, 1722, 1698, 1525, 1362, 1348, 1181, 1174, 1159.

Process 2

A solution of 13.29 g (37.08 mmol) of compound (XX-1) in 200 ml of methanol was hydrogenated using 10% Pd/C (1 g) for 2h at room temperature. The reaction mixture was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from acetone/n-hexane to give 11.5 g of amine derivative (XXI-1).

Yield 94.4%. mp. 164-166° C.

Elemental analysisC₁₅H₂₄N₂O₄S Calcd.: C; 54.86 H; 7.37 N; 8.53 S; 9.76 Found: C; 54.84 H; 7.33 N; 8 63 S; 9.50

[α]_(D) +10.3±1.0(c=0.515 DMSO 23° C.)

IR(KBr, υ max cm⁻¹): 3461, 3375, 1716, 1638, 1598, 1344, 1313.

NMR(d-DMSO, δ ppm): 0.80(d, J=6.8 Hz, 3H), 0.82(d, J=6.6 Hz, 3H), 1.23(s, 9H), 1.83(m, 1H), 3.30(m, 1H), 5.86(s, 2H), 6.56(d, J=8.8 Hz, 2H), 7.36(d, J=8.6 Hz, 2H), 7.47(d, J=9.6 Hz, 1H)

Process 3

To a solution of 328 mg (1 mmol) of compound (XXI-1) in 10 ml of dichloromethane was added 0.33 ml (3×1 mmol) of N-methylmorpholine and 280 mg (1.5×1 mmol) of 4-(methylthio)benzoyl chloride under ice-cooling. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was added ethyl ether and precipitation were collected and washed with ice-water and ethyl ether, The solid were recrystallized from acetone/ethyl ether to give 433 mg of the desired compound (XXII-1).

Yield 90.5%. mp. 235-238° C.

Elemental analysisC₂₃H₃₀N₂O₅S₂ Calcd. : C; 57.72 H; 6.32 N; 5.85 S; 13.40 Found: C; 57.63 H; 6.28 N; 5.86 S; 13.20

[α]_(D) +5.7±0.9(c=0.512 DMSO 25° C.)

IR(KBr, υ max cm⁻¹): 3366, 3284, 1713, 1667, 1592, 1514, 1498, 1341, 1317.

NMR(d₆-DMSO, δ ppm) : 0.82(d, J=6.6 Hz, 3H), 0.84(d, J=6.8 Hz, 3H), 1.22(s, 9H), 1.91(m, 1H), 2.55(s, 3H), 3.32(s, 3H), 3.44(dd, J=6.2, 8.6 Hz, 1H), 7.40(d, J=8.6 Hz, 2H), 7.73(d, J=8.6 Hz, 2H), 7.90-8.01(m, 5H), 10.48 (s, 1H).

Process 4

To a solution of 405 mg (0.85 mmol) of compound (XXII-1) in 3 ml of dichloromethane was added 3.3 ml (50×0.85 mmol) of trifluoroacetic acid and resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was washed with ethyl ether to give 340 mg of the desired compound (Ia-4-1).

Yield 94.7%. mp. 231-234° C.

IR(KBr, υ max cm⁻¹): 1748, 1655, 1592, 1323, 1161.

Elemental analysis C₁₉H₂₂N₂O₅S₂ . 0.1CF₃COOH Calcd. : C; 53.14 H; 5.13 N; 6.46 S; 14.78 Found: C; 53.48 H; 5.31 N; 6.57 S; 15.06

EXAMPLE 177-208

The compounds which were shown in Tables 33 to 36 were synthesized in a manner similar to those described in Example 176.

TABLE 33 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 177

R 215-217 1732, 1641 1341, 1163 — 178

R 233-234 1726, 1655 1323, 1177 C₂₅H₂₃N₃O₆S.0.9H₂O Calc. C:58.91 H:4.90 N:8.24 S:6.29 Foun. C:58.97 H:5.07 N:7.95 S:6.10 179

R 216-218 1723, 1633 1361, 1149 — 180

R 211-213 1719, 1629 1340, 1156 C₂₄H₂₀N₄O₇S.1.1H₂O Calc. C:54.56 H:4.24 N:10.60 S:6.07 Foun. C:54.51 H:4.32 N:10.83 S:6.15 181

R 236-238 1732, 1653 1399, 1199 C₂₆H₂₆N₄O₅S.0.9H₂O Calc. C:59.73 H:5.36 N:10.72 S:6.13 Foun. C:59.58 H:5.23 N:10.75 S:6.47 182

R 240-244 1731, 1656 1591, 1327 1160 C₂₅H₂₃N₃O₅S.0.9H₂O Calc. C:60.82 H:5.06 N:8.51 S:6.49 Foun. C:60.83 H:5.19 N:8.66 S:6.66 183

R 215-218 1727, 1668 1590, 1316 1154 C₂₄H₂₀BrN₃O₅S.0.6H₂O Calc. C:52.11 H:3.86 Br:14.44 N:7.60 S:5.80 Foun. C:52.13 H:4.04 Br:14.57 N:7.43 S:5.70 184

R 244-249 1728, 1653 1593, 1323 1159 C₂₅H₂₃N₃O₅S₂.0.7H₂O Calc. C:57.50 H:4.71 N:8.05 S:12.28 Foun. CL57.63 H:4.79 N:8.00 S:12.08

TABLE 34 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 185

R 170-175 1730, 1651 1603, 1333 1161 C₂₄H₂₀FN₃O₅S.0.6H₂O Calc. C:58.55 H:4.34 F:3.86 N:8.54 S:6.51 Foun. C:58.67 H:4.51 F:3.77 N:8.42 S:6.47 186

R 237-239 1723, 1651 1591, 1322 1161 C₂₃H₂₂N₂O₆S Calc. C:60.78 H:4.88 N:6.16 S:7.05 Foun. C:60.50 H:4.99 N:6.14 S:7.31 187

R 235-239 1719, 1672 1593, 1327 1159 C₂₂H₁₉N₃O₇S Calc. C:56.29 H:4.08 N:8.95 S:6.83 Foun. C:56.01 H:4.09 N:8.93 S:6.75 188

R 114-115 1748, 1658 1592, 1325 1159 C₂₂H₂₀N₂O₅S.0.5CF₃COOH Calc. C:57.37 H:4.29 N:5.82 S:6.66 Foun. C:57.53 H:4.45 N:5.75 S:7.11 189

R 242-243 1743, 1670 1591, 1335 1167 C₂₂H₁₉BrN₂O₅S.CF₃COOH Calc. C:46.69 H:3.27 Br:12.94 N:4.54 S:5.19 Foun. C:46.79 H:3.41 Br:12.86 N:4.57 S:5.37 190

R 242-244 1752, 1726 1656, 1591 1324, 1160 C₂₃H₂₂N₂O₅S Calc. C:63.00 H:5.06 N:6.39 S:7.31 Foun. C:62.70 H:5.13 N:6.36 S:7.36 191

R 232-235 1742, 1667 1591, 1334 1161 C₂₃H₂₂N₂O₅S₂.0.8CF₃COOH Calc. C:52.59 H:4.09 N:4.99 S:11.42 Foun. C:52.77 H:4.24 N:5.12 S:11.58 192

R 218-220 1737, 1651 1598, 1324 1160 C₂₂H₁₉FN₂O₅S Calc. C:59.72 H:4.33 F:4.29 N:6.33 S:7.25 Foun. C:59.59 H:4.42 F:4.30 N:6.37 S:7.24

TABLE 35 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 193

R 201-203 1724, 1673 1592, 1326 1156 C₂₁H₁₈ClN₃O₅S Calc. C:54.84 H:3.94 Cl:7.71 N:9.14 S:6.97 Foun. C:54.39 H:4.06 Cl:7.42 N:8.98 S:6.99 194

R 206-208 1725, 1682 1592, 1332 1160 C₂₂H₂₀ClN₃O₅S.0.1CF₃COOH Calc. C:55.15 H:4.19 Cl:7.33 N:8.69 S:6.63 Foun. C:55.25 H:4.28 Cl:7.10 N:8.80 S:6.80 195 (CH₃)₂CH—

R 254-256 1748, 1659 1590, 1324 1161 C₂₄H₂₄N₂O₅S.0.5H₂O Calc. C:62.46 H:5.46 N:6.07 S:6.95 Foun. C:62.42 H:5.54 N:6.26 S:6.97 196 (CH₃)₂CH—

R 227-229 1749, 1658 1592, 1323 1161 C₁₉H₂₂N₂O₅S.0.2H₂O Calc. C:57.91 H:5.73 N:7.11 S:8.14 Foun. C:57.94 H:5.69 N:7.03 S:8.14 197 (CH₃)₂CH—

R 231-234 1748, 1655 1592, 1323 1161 C₁₉H₂₂N₂O₅S₂0.1CF₃COOH Calc. C:53.14 H:5.13 N:8.46 S:14.78 Foun. C:53.48 H:5.31 N:6.57 S:15.06 198 (CH₃)₂CH—

R 235-236 1749, 1726 1668, 1597 1322, 1160 C₁₈H₁₉FN₂O₅S.0.1CF₃COOH Calc. C:53.86 H:4.74 F:6.09 S:7.90 Foun. C:53.82 H:4.85 F:5.60 N:6.93 S:7.78 199 (CH₃)₂CH—

R 226-227 1728, 1661 1591, 1317 1159 C₁₈H₂₀N₂O₅S.0.1H₂O Calc. C:57.16 H:5.38 N:7.41 S:8.48 Foun. C:57.01 H:5.46 N:7.57 S:8.57 200 (CH₃)₂CH—

R 220-221 1696, 1654 1591, 1317 1255 C₁₉H₂₂N₂O₆S.0.2H₂O Calc. C:55.65 H:5.51 N:6.83 S:7.82 Foun. C:55.63 H:5.48 N:7.03 S:7.75

TABLE 36 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 201 (CH₃)₂CH—

R 240-242 1726, 1688 1591, 1347 1166 C₁₈H₁₉N₃O₇S.0.4H₂O Calc. C:50.44 H:4.66 N:9.80 S:7.48 Foun. C:50.40 H:4.55 N:9.90 S:7.44 202 (CH₃)₂CH—

R 229-230 1726, 1663 1592, 1318 1159 C₁₈H₁₉BrN₂O₅S.0.2Ethylether Calc. C:48.03 H:4.50 Br:17.00 N:5.96 S:6.82 Foun. C:48.04 H:4.61 Br:16.83 N:5.96 S:6.86 203 (CH₃)₃C—

R 214-216 1659, 1591 1316, 1159 C₂₀H₂₄N₂O₆S.0.4H₂O Calc. C:56.17 H:5.84 N:6.55 S:7.50 Foun. C:56.21 H:6.02 N:6.50 S:7.33 204

R 236-237 1723, 1679 1590, 1337 1162 C₂₁H₂₀N₄O₅S.0.25CF₃COOH Calc. C:55.06 H:4.35 N:11.95 S:6.84 Foun. C:54.80 H:4.90 N:12.18 S:7.10 205

R 272-275 1719, 1672 1590, 1337 1165 C₂₁H₁₉N₃O₅S Calc. C:59.28 H:4.50 N:9.88 S:7.54 Foun. C:58.84 H:4.56 N:9.71 S:7.38 206

R 214-215 1733, 1685 1594, 1319 1154 C₂₀H₁₉N₃O₆S Calc. C:55.94 H:4.46 N:9.78 S:7.47 Foun. C:55.50 H:4.47 N:9.74 S:7.31 207

R 217-220 1732, 1679 1592, 1312 1155 — 208

R — — —

EXAMPLE 209

(Method E)

Process 1

To a solution of 20.94 g (99.8 mmol) of D-valine tert-butyl ester hydrochloride (XV-3) in 200 ml of dichloromethane was added 22 ml (2×99.8 mmol) of N-methylmorpholine and 20.27 g (99.8 mmol) of p-styrenesulfonyl chloride under ice-cooling. After being stirred for 15 h at room temperature, the reaction mixture was washed with 2N HCl, 5% NaHCO₃, water. The organic layer was dried over Na2SO4 and concentrated in vacuo, and the resulting residue was column chromatographed on silica gel. The fractions eluting with ethyl acetate/n-hexane/chloroform=1/3/1 were collected and washed with n-hexane to give 28.93 g of the desired compound (XXIII-1).

Yield 85%. mp. 118-120° C.

IR(KBr, υ max cm⁻¹): 3419, 3283, 1716, 1348, 1168.

NMR(CDCl₃, δ ppm): 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.6 Hz, 3H), 1.21(s, 9H), 2.04(m, 1H), 3.62(dd, J=9.8, 4.5 Hz, 1H), 5.09(d, J=9.8 Hz, 1H), 5.41(dd, J=0.5, 10.9 Hz, 1H), 5.84(dd, J=0.5, 17.6 Hz, 1H), 6.72(dd, J=10.9, 17.6 Hz, 1H), 7.49(d, J=8.4 Hz, 2H), 7.79(d, J=8.4 Hz, 2H).

Process 2

Ozone gas was bubbled through a solution of 5.09 g (15 mmol) of compound (XXIII-1) in 300 ml of dichloromethane for 15 h at −78° C. To this solution was added 22 ml (20×15 mmol) of methylsulfide, and the reaction mixture was allowed to warm to room temperature gradually over 80 min and concentrated in vacuo to give 6.03 g aldehyde derivative (XXIV-1).

IR(CHCl₃, υ max cm⁻¹): 3322, 1710, 1351, 1170.

NMR(CDCl₃, δ ppm): 0.85(d, J=6.9 Hz, 3H), 1.00(d, J=6.9 Hz, 3H), 1.22(s, 9H), 2.07(m, 1H), 3.69(dd, J=4.5, 9.9 Hz, 1H), 8.01(s, 4H), 10.08(s, 1H).

Process 3

To a solution of 6.02 g(l5 mmol) of compound (XXIV-1) in 60 ml of ethanol and 15 ml of tetrahydrofuran was added 2.72 g (1.05×15 mmol) of benzenesulfonyl hydrazide at room temperature. After being stirred for 2 h, the resulting mixture was concentrated in vacuo. The residue which was obtained by concentration in vacuo was column chromatographed on silica gel and the fractions eluting with chloroform/ethyl acetate=¼ were collected and recrystallized from ethyl acetate to give 4.44 g of the desired compound (XXV-1). Yield from process 2 60%. mp. 163-164° C.

Elemental analysis C₂₂H₂₉N₃O₆S₂ Calcd. : C; 53.32 H; 5.90 N; 8.48 S; 12.94 Found: C; 53.15 H; 5.87 N; 8.32 S; 12.82

[α]_(D) −11.6±1.0(c=0.509 DMSO 23.5° C.)

IR(KBr, υ max cm⁻¹): 3430, 3274, 1711, 1364, 1343, 1172.

NMR(CDCl₃ δ ppm): 0.84(d, J=6.9 Hz, 3H), 0.99(d, J=6.6 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 3.63(dd, J=4.5, 9.9 Hz, 1H), 5.16(d, J=9.9 Hz, 1H), 7.50-7.68(m, 5H), 7.73(s, 1H), 7.78-7.84(m, 2H), 7.96-8.02(m, 2H), 8.16(brs, 1H).

Process 4

To a solution of 0.14 ml (1.11×1 mmol) of 4-(methylmercapto)aniline and 0.3 ml of conc. hydrochloric acid in 3 ml of aqueous 50% ethanol solution was added a solution of 78.4 mg (1.14×1 mmol) of sodium nitrite in 1 ml of water at 0 to 5° C. of the internal temperature and the reaction mixture was stirred for 15 min at the same temperature. To a solution of 496 mg (1 mmol) of compound (XXV-1) in 5 ml of dry pyridine was added the above reaction mixture over 8 min at −25° C. This reaction mixture was stirred for additional 4 h at −1520 C. to rt, poured into water, and extracted with ethyl acetate. The organic layer was washed with 2N HCl, 5% NaHCO₃, and water, dried over Na₂SO₄, and concentrated in vacuo. The residue was column chromatographed on silica gel and the fractions eluting with chloroform/ethyl acetate={fraction (1/9)} were collected to give 374 mg of the desired compound (XXVI-1).

Yield 74%.

Elemental analysis C₂₃H₂₉N₅O₄S₂.0.3H₂O Calcd. : C; 54.27 H; 5.86 N; 13.76 S; 12.60 Found: C; 54.25 H; 5.77 N; 13.87 S; 12.52

IR(KBr, υ max cm⁻¹): 3422, 3310, 1705, 1345, 1171.

NMR(d₆-DMSO, δ ppm) : 0.83(d, J=6.9 Hz, 3H), 0.86(d, J=7.2 Hz, 3H), 1.19(s, 9H), 2.00(m, 1H), 2.59(s, 3H), 3.54(dd, J=6.3, 9.6 Hz, 1H), 7.56(d, J=8.7 Hz, 2H), 8.00(d, J=8.6 Hz, 2H), 8.10(d, J=8.7 Hz, 2H), 8.33(d, J=9.6 Hz, 2H), 8.34(d, J=8.7 Hz, 2H).

Process 5

A solution of 353 mg of compound (XXVI- 1) in 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid was stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the resulting residue was washed with ethyl ether to give 308 mg of compound (Ia-5-1).

Yield98%. mp. 194-195° C.

IR(KBr, υ max cm⁻¹): 1720, 1343, 1166.

Elemental analysis C₁₉H₂₁N₅O₄S₂ . 1.1H₂O Calcd. : C; 48.83 H; 5.00 N; 14.99 S; 13.72 Found: C; 49.13 H; 5.25 N; 14.55 S; 13.34

EXAMPLE 210-251

The compounds which were shown in Tables 37 to 43 were synthesized in a manner similar to those described in Example 209.

TABLE 37 (Ib)

Example No. R¹ R¹⁸ * 210

R 211

R Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (° C.) (KBr) d₆-DMSO 210 — — — 211 194-195 3700-2200(br), 3278, 2.65(dd, J=9.3, 13.1Hz, 1H), 2.82(dd, 1634, 1337, 1160 J=5.8, 13.1Hz, 1H), 3.86(dt, J=5.8, 9.3 Hz, 1H), 7.72(A₂B₂q, J=8.1Hz, 2H), 8.19(A₂B₂q, J=8.1Hz, 2H), 8.49(d, J= 9.3Hz, 1H), 8.88(s, 1H), 10.69(s, 1H)

TABLE 38 (Ia)

Example No. R¹ R¹⁸ * 210

R 211

R Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (° C.) (KBr) d₆-DMSO 210 — — — 211 215-216 2400-3700br, 3422, 3337, 2.75(dd, J=9.3, 13.7Hz, 1H), 2.99 1733, 1698, 1347, 1170 (dd, J=5.3, 13.7Hz, 1H), 3.96(dt, J= 5.3, 9.3Hz, 1H), 8.53(d, J=9.3Hz, 1H)

TABLE 39 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 212

RS 199-202 1734, 1337 1161 C₂₅H₂₂N₆O₄S.0.5Ethylether Calc. C:60.10 H:5.04 N:15.57 S:5.94 Foun. C:60.41 H:4.69 N:15.52 S:5.57 213

RS 224-225 1728, 1338 1166 C₂₄H₁₉FN₆O₄S.0.4Ethylether Calc. C:57.35 H:4.32 F:3.54 N:15.67 S:5.98 Foun. C:56.74 H:4.37 F:3.47 N:15.17 S:568 214 (CH₃)₂CHCH₂—

R 202-204 1720, 1595 1338, 1170 C₁₉H₂₁N₅O₄S Calc. C:54.93 H:5.09 N:16.86 S:7.72 Foun. C:54.75 H:5.14 N:16.81 S:7.55 215 (CH₃)₂CH—

R 221-22 1696, 1594 1349, 1173 C₁₈H₁₉N₅O₄S Calc. C:53.38 H:4.83 N:17.29 S:7.92 Foun. C:53.38 H:4.80 N:17.05 S:7.67 216

RS 145-148 1727, 1337 1163 — 217

R 203-205 1735, 1495 1336, 1160 C₂₈H₂₃N₅O₄S.0.6H₂O Calc. C:62.70 H:4.55 N:13.06 S:5.98 Foun. C:62.61 H:4.50 N:13.29 S:5.87 218

RS 225-227 1721, 1418 1344, 1163 C₂₆H₂₁N₅O₄S.0.2H₂O Calc. C:62.07 H:4.29 N:13.92 S:6.37 Foun. C:61.93 H:4.30 N:14.01 S:6.43 219

R 111-114 1727, 1703 1459, 1332 1165 C₂₅H₂₀N₆O₅S.H₂O Calc. C:56.17 H:4.15 N:15.72 S:6.00 Foun. C:56.20 H:4.18 N:15.68 S:6.10

TABLE 40 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 220

R 195-196 1749, 1719 1331, 1165 C₂₅H₂₂N₆O₅S Calc. C:57.91 H:4.28 N:16.21 S:6.18 Foun. C:57.77 H:4.29 N:16.01 S:6.37 221 CH₃CH₂(CH₃)CH—

R 205-207 1730, 1693 1349, 1173 C₁₉H₂₁N₅O₄S Calc. C:54.93 H:5.09 N:16.86 S:7.72 Foun. C:54.71 H:5.09 N:16.70 S:7.56 222 CH₃CH₂(CH₃)CH—

R 204-207 1729, 1693 1337, 1170 C₂₀H₂₃N₅O₅S.0.4H₂O Calc. C:53.06 H:5.30 N:15.47 S:7.08 Foun. C:53.13 H:5.13 N:15.12 S:7.14 223 (CH₃)₂CH—

R 190 decomp. 1718, 1601 1385, 1162 — 224 (CH₃)₂CH—

R 195-197 1719, 1304 1162 C₂₀H₂₃N₅O₅S.0.4H₂O Calc. C:53.06 H:5.30 N:15.47 S:7.08 Foun. C:53.13 H:5.13 N:15.12 S:7.14 225 (CH₃)₂CH—

R 227-228 1696, 1348 1171 C₁₈H₁₈BrN₅O₄S.0.8H₂O Calc. C:43.70 H:3.99 Br:16.15 N:14.16 S:6.48 Foun. C:43.93 H:3.85 Br:15.92 N:13.87 S:6.47 226 (CH₃)₃C—

R 204-207 1698, 1344 1168 — 227

R 203-205 1757, 1738 1331, 1163 —

TABLE 41 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 228

R 197-199 1744, 1325 1154 — 229

R 197-198 1738, 1707 1328, 1169 C₂₃H₁₈F₃N₅O₄S Cacl. C:53.38 H:3.51 F:11.01 N:13.53 S:6.20 Foun. C:53.11 H:3.55 F:10.89 N:13.66 S:6.31 230

R 190-191 1730, 1597 1345, 1161 C₂₂H₁₈N₆O₆S.0.4H₂O Calc. C:52.67 H:3.78 N:16.73 S:6.39 Foun. C:52.73 H:3.92 N:16.53 S:6.55 231

R 205-207 1730, 1509 1236, 1165 C₂₂H₁₈FN₅O₄S.0.2H₂O Calc. C:56.09 H:3.94 F:4.03 N:14.87 S:6.81 Foun. C:56.10 H:4.09 F:4.12 N:14.84 S:7.08 232

R 204-206 1730, 1493 1346, 1164 C₂₂H₁₈ClN₅O₄S.0.6H₂O Calc. C:53.41 H:3.91 Cl:7.17 N:14.16 S:6.48 Foun. C:53.33 H:3.90 Cl:7.22 N:14.19 S:6.68 233

R 226-227 1732, 1697 1509, 1373 1345, 1170 C₂₃H₂₁N₅O₄S.1.2H₂O Calc. C:56.94 H:4.86 N:14.44 S:6.61 Foun. C:56.88 H:4.49 N:14.31 S:6.72 234

R 214-216 1732, 1697 1345, 1168 C₂₃H₂₁N₅O₅S.1.7H₂O Calc. C:54.15 H:4.82 N:13.73 S:6.29 Foun. C:54.05 H:4.35 N:13.60 S:6.77 235

R 190-192 1731, 1605 1336, 1160 C₂₃H₁₈N₆O₄S.0.8H₂O Calc. C:56.50 H:4.04 N:17.19 S:6.56 Foun. C:56.52 H:4.16 N:17.00 S:6.52

TABLE 42 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 236

R 224-226 1738, 1328 1314, 1149 C₂₆H₂₇N₅O₄S Calc. C:61.77 H:5.38 N:13.85 S:6.34 Foun. C:61.59 H:5.45 N:13.89 S:6.27 237

R 225-227 1739, 1512 1329, 1178 C₂₈H₂₉N₅O₄S.0.3H₂O Calc. C:62.62 H:5.56 N:13.04 S:5.97 Foun. C:62.46 H:5.52 N:13.43 S:6.28 238

R 182-184 1587, 1506 1242, 1159 — 239

R 226-228 1713, 1514 1341, 1159 — 240

R 205-207 1744, 1716 1490, 1317 1159 C₂₄H₁₉BrN₆O₄S.1.7H₂O Calc. C:48.20 H:3.78 Br:13.36 N:14.05 S:5.36 Foun. C:48.27 H:3.75 Br:13.16 N:14.11 S:5.38 241

R 199-201 1718, 1685 1334, 1170 C₂₅H₂₂N₆O₄S.0.6H₂O Calc. C:58.49 H:4.56 N:16.37 S:6.25 Foun. C:58.52 H:4.69 N:16.71 S:5.90 242 (CH₃)₂CH—

R 206-207 1716, 1346 1165 C₁₉H₂₁N₅O₄S.0.8H₂O Calc. C:53.09 H:5.30 N:16.29 S:7.48 Foun. C:53.20 H:5.14 N:16.06 S:7.70 243 (CH₃)₂CH—

R 208-209 1746, 1726 1715, 1334 1159 C₁₈H₁₈FN₅O₄S.0.2H₂O Calc. C:51.11 H:4.38 F:4.49 N:16.55 S:7.58 Foun. C:50.90 H:4.37 F:4.89 N:16.28 S:7.46

TABLE 43 (Ia)

Example mp (decomp.) IR (ν cm⁻¹) No. R¹ R¹⁸ * (° C.) (KBr) Elemental analysis 244 (CH₃)₂CH—

R 223-225 1696, 1348 1171 — 245 (CH₃)₂CH—

R 194-195 1720, 1343 1166 C₁₉H₂₁N₅O₄S₂.1.1H₂O Calc. C:48.83 H:5.00 N:14.99 S:13.72 Foun. C:49.13 H:5.25 N:14.55 S:13.34 246

R 222-224 1753, 1497 1325, 1165 C₂₃H₂₁N₅O₄S₂.0.2H₂O Calc. C:55.34 H:4.32 N:14.03 S:12.85 Foun. C:55.37 H:4.35 N:14.00 S:12.86 247

R 213-216 1718, 1677 1495, 1333 1170 C₂₅H₂₂N₆O₄S₂.1.1H₂O Calc. C:54.16 H:4.40 N:15.16 S:11.57 Foun. C:54.20 H:4.66 N:15.09 S:11.62 248

R >220 1698, 1430 1327, 1163 C₁₈H₁₆N₆O₄S.0.4H₂O Calc. C:51.52 H:4.04 N:20.03 S:7.64 Foun. C:51.34 H:3.96 N:19.76 S:8.02 249

R — — — 250

R — — — 251

R — — —

EXAMPLE 252-266

The compounds which were shown in Tables 44 to 45 were synthesized in a manner similar to those described in Example 157.

TABLE 44 (I)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ R¹⁹ R²⁰ * (° C.) (KBr) d₆-DMSO 252 (CH₃)₂CH—

—CH₃ —COOH R — 1715, 1583 1340, 1151 0.96(d, J=6.6Hz, 3H) 1.01(d, 6.8Hz, 3H) 2.87(s, 3H) 4.17(d, J=10.4Hz, 1H) 253 (CH₃)₂CH—

—CH₃ —CONHOH R 110-111 3323, 1678 1328, 1150 0.71(d, J=6.6Hz, 3H) 0.88(d, 6.4Hz, 3H) 2.88(s, 3H) 3.48(d, J=10.8Hz, 1H) 254 (CH₃)₂CH—

—CONHOH R 148-150 3344, 1684 1323, 1149 0.55(d, J=6.8Hz, 3H) 0.82(d, 6.6Hz, 3H) 3.74(s, 3H) 255 (CH₃)₂CH—

—(CH₂)₄NH₂ —COOH R — 3700-2200br 1681, 1319 1212 0.91(d, J=5.6Hz, 6H) 1.52-1.69(m, 4H) 3.84(d, J=10.4Hz, 1H) 256 (CH₃)₂CH—

—CH₃ —COOH R 206-207 3300-2400br 1711, 1336 1185 0.95(d, J=6.6Hz, 3H) 0.97(d, 6.8Hz, 3H) 2.89(s, 3H) 4.20(d, J=10.6Hz, 1H) 257 (CH₃)₂CHCH₂—

—CH₃ —COOH R   132-132.5 3300-2400br 1719, 1340 1153 0.92(d, J=6.6Hz, 3H) 0.97(d, 6.6Hz, 3H) 2.84(s, 3H) 4.73(t, J=7.4Hz, 1H) 258

—COOH R — 3640-2400br 1736, 1717 1694, 1346 1162 2.78(d.d, J=13.8, 7.2Hz, 1H) 3.14(d.d, J=14.8, 7.4Hz, 1H) 4.43(d, J=16.4Hz, 1H) 4.68(d, J=16.4Hz, 1H) 259 (CH₃)₂CH—

—CH₃ —COOH R 141-144 3284br, 1745 1714, 1323 1131 0.96(d, J=6.4Hz, 3H) 0.97(d, J=6.4Hz, 3H) 2.52(s, 3H), 2.93(s, 3H)

TABLE 45 (I)

Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. R¹ R¹⁸ R¹⁹ R²⁰ * (° C.) (KBr) d₆-DMSO 260 (CH₃)₂CH—

—COOH R — 3600-2400br 1718, 1344 1151 0.72(d, J=6.4Hz, 3H)0.85(d, J=6.4Hz, 3H), 2.47(s, 3), 4.15(d, J=10.2Hz, 1H)4.51(d, J=15.5 Hz, 1H),4.73(d. J=15.5Hz, 1H) 261

—CH₃ —COOH R — 3600-2400br 1719, 1655 1592, 1320 1154 2.54(s. 3H), 2.78(s, 3H) 2.85(d.d, J=14.0, 9.4Hz, 1H) 3.16(d.d, J=14.0, 6.0Hz, 1H) 4.76(d.d, J=10.0, 5.8Hz, 1H) 262

—COOH R — — — 263

—(CH₂)₄NH₂ —COOH R — — — 264

—CH₃ —COOH R — — — 265

—COOH R — — — 266

—(CH₂)₄NH₂ —COOH R — — —

EXAMPLE 267

The compounds which were shown in Tables 46 were synthesized in a manner similar to those described in Example 92.

TABLE 46 (I)

Example No. R¹ R¹⁸ R²⁰ * 267

—CONHOH R 268

—COOH R Example mp (decomp.) IR (ν cm⁻¹) ¹H-NMR (δ ppm) No. (° C.) (KBr) d₆-DMSO 267 156-158 3700-2400br, 3267, 2.62(dd, J=8.4, 13.5Hz, 1H), 2.80(dd, 2217, 1671, 1321, 1161 J=6.0, 13.5Hz, 1H), 3.82(ddd, J=6.0, 8.4, 8.7Hz, 1H), 8.38(d, J=8.7Hz, 1H) 267 176-178 2200-3700br, 3430, 2.73(dd, J=9.3, 13.6Hz, 1H), 2.96(dd, 3292, 1728, 1324, 1162 J=5.4, 13.5Hz, 1H), 3.92(dt, J=5.4, 9.3Hz, 1H), 8.42(d. J=9.3Hz, 1H)

Test examples on the compounds of the present invention are described below. The test compounds are the ones described in the Examples and Tables.

Test example

(1) Isolation and purification of MMP-9 (92 kDa, gelatinase B)

Type IV collagenase (MMP-9) was purified according to the methods described in the following literature. Scott M. Wilhelm et al., J. Biol. Chem., 264, 17213-17221, (1989), SV40-transformed Human Lung Fibroblasts Secrete a 92-kDa Type IV Collagenase Which Is Identical to That Secreted by Normal Human Macrophages; Yasunori Okada et al., J. Biol. Chem., 267, 21712-21719, (1992), Matrix Metalloproteinase 9 (92-kDa Gelatinase/Type IV Collagenase) from HT 1080 Human Fibrosarcoma Cells; Robin V. Ward et al., Biochem. J., (1991) 278, 179-187, The purification of tissue inhibitor of metalloproteinase-2 from its 72 kDa progelatinase complex.

MMP-9 is secreted from human fibrosarcoma cell line ATCC HT 1080, into its culture medium when it is stimulated with 12-tetradecanoylphorbol-13-acetate (TPA). The production of MMP-9 in this culture was verified by the gelatin zymography as described in the following literature (Hidekazu Tanaka et al., (1993) Biochem. Biophys. Res. Commun., 190, 732-740, Molecular cloning and manifestation of mouse 105-kDa gelatinase cDNA). The condition medium of the stimulated HT 1080 was concentrated and was purified with gelatin-Sepharose 4B, concanavalin A-sepharose, and Sephacryl S-200. The purified pro-MMP-9 (92 kDa, gelatinase B) thus obtained gave a single positive band in the gelatin zymography. Subsequently, activated MMP-9 was obtained by treating the pro-MMP-9 with trypsin.

(2) Assay methods of type IV collagenase inhibitors

Collagenase assay was performed using the activated MMP-9 described above and the substrate supplied in the type IV collagenase activity kit (YAGAI, inc.), according to the manufacturer's protocol. The following 4 assays are performed per compound (inhibitor).

(A) substrate (type IV collagenase), enzyme (MMP-9), inhibitor

(B) substrate (type IV collagenase), inhibitor

(C) substrate (type IV collagenase), enzyme (MMP-9)

(D) substrate (type IV collagenase)

According to the manufacturer's protocol, fluorescent intensity was measured and percent inhibition was determined by the following equation.

Inhibition (%)={1−(A−B)/(C−D))×100

IC₅₀ is a concentration at which the percent inhibition reaches 50%. The results are shown in Tables 47 to 54.

TABLE 47 Example No. Compound No. IC₅₀ (μM) Compound No. IC₅₀ (μM) 1 1a-1-1  0.24 1b-1-1  0.030 2 1a-1-2  2.6 1b-1-2  0.04 3 1a-1-3  0.18 1b-1-3  0.005 4 1a-1-4  2.25 5 1a-1-5  0.81 1b-1-5  0.041 6 1a-1-6  0.68 1b-1-6  0.034 7 1b-1-7  0.028 8 1a-1-8  2.0 1b-1-8  2.0 9 1b-1-9  0.41 10 1b-1-10 2.1 11 1b-1-11 1.7 12 1b-1-12 0.085 13 1b-1-13 0.38 14 1a-1-14 3.7 1b-1-14 0.11 15 1b-1-15 0.027 16 1a-1-16 0.520 1b-1-16 0.0108 17 1a-1-17 0.205 1b-1-17 0.0203 18 1a-1-18 0.500 1b-1-18 0.0282 20 1b-1-20 0.134 21 1a-1-21 4.65 1b-1-21 0.0041 23 1b-1-23 0.073 24 1b-1-24 0.2 26 1b-1-26 1.3 27 1b-1-27 3.0 30 1a-1-30 1.16 1b-1-30 0.213 31 1b-1-31 0.0129

TABLE 48 Example No. Compound No. IC₅₀ (μM) Compound No. IC₅₀ (μM) 33 1a-1-33 0.24 1b-1-33 0.005 35 1a-1-35 2.6 1b-1-35 0.0216 38 1a-1-38 0.018 40 1a-1-40 0.076 41 1a-1-41 0.312 42 1a-1-42 0.0123 43 1a-1-43 0.625 44 1a-1-44 1.910 45 1a-1-45 0.040 46 1a-1-46 1.12 47 1a-1-47 0.389 48 1a-1-48 1.15 49 1a-1-49 0.249 50 1a-1-50 0.553 51 1a-1-51 0.110 52 1a-1-52 0.329 53 1a-1-53 1.8 54 1a-1-54 0.075 55 1a-1-55 0.0398 60 1a-1-60 1.31 1b-1-60 0.0012 61 1a-1-61 0.247 1b-1-61 0.247 62 1b-1-62 3.50 63 1a-1-63 1.05 1b-1-63 0.00039 64 1a-1-64 1.90 1b-1-64 0.0037 65 1a-1-65 0.291 1b-1-65 0.0035

TABLE 49 Example No. Compound No. IC₅₀ (μM) Compound No. IC₅₀ (μM) 67 1a-1-67 1b-1-67 0.0061 68 1a-1-68 0.231 80 1a-1-80 1.91 83 1a-1-83 1.77 85 1a-1-85 1.2 1b-1-85 0.013 86 1a-1-86 0.35 1b-1-86 0.0053 87 1b-1-87 0.940 93 1a-2-2  0.237 94 1a-2-3  0.0109 95 1a-2-4  0.0759 96 1a-2-5  0.123 97 1a-2-6  0.088 98 1a-2-7  0.0699 100 1a-2-9  0.0577 101 1a-2-10 0.023 102 1a-2-11 0.0475 103 1a-2-12 0.0981 104 1a-2-13 3.28 105 1a-2-14 2.98 106 1a-2-15 0.133 107 1a-2-16 0.325 109 1a-2-18 1.19 110 1a-2-19 0.203 111 1a-2-20 3.41 112 1a-2-21 3.74 114 1a-2-23 0.929

TABLE 50 Example No. Compound No. IC₅₀ (μM) 115 1a-2-24 0.161 117 1a-2-26 1.19 118 1a-2-27 0.088 119 1a-2-28 1.11 120 1a-2-29 1.53 121 1a-2-30 0.0736 122 1a-2-31 0.224 123 1a-2-32 0.0234 124 1a-2-33 0.0218 125 1a-2-34 0.0144 126 1a-2-35 0.156 127 1a-2-36 0.0243 128 1a-2-37 0.0922 129 1a-2-38 0.222 160 1a-3-2  0.040 161 1a-3-3  0.0108 162 1a-3-4  0.873 163 1a-3-5  0.0126 164 1a-3-6  0.0965 165 1a-3-7  0.230 166 1a-3-8  1.28 167 1a-3-9  0.014 168 1a-3-10 0.0083 169 1a-3-11 0.244 170 1a-3-12 2.03 171 1a-3-13 0.0395

TABLE 51 Example No. Compound No. IC₅₀ (μM) 177 1a-4-2  0.684 178 1a-4-3  0.0252 179 1a-4-4  2.36 180 1a-4-5  0.045 181 1a-4-6  0.0539 182 1a-4-7  0.0059 183 1a-4-8  0.0027 184 1a-4-9  0.00325 185 1a-4-10 0.0422 186 1a-4-11 0.0982 187 1a-4-12 0.177 188 1a-4-13 0.843 189 1a-4-14 0.0375 190 1a-4-15 0.0597 191 1a-4-16 0.0095 192 1a-4-17 0.324 193 1a-4-18 0.722 195 1a-4-20 1.1 196 1a-4-21 0.0573 197 1a-4-22 0.0161 198 1a-4-23 0.493 199 1a-4-24 2.06 200 1a-4-25 0.173 201 1a-4-26 0.252 202 1a-4-27 0.0114 203 1a-4-28 0.173

TABLE 52 Example No. Compound No. IC₅₀ (μM) Compound No. IC₅₀ (μM) 204 1a-4-29 3.95 207 1a-4-30 4.44 210 1a-5-2  0.024 211 1a-5-3  0.210 1b-211 0.00565 212 1a-5-4  0.393 213 1a-5-5  0.128 214 1a-5-6  0.832 215 1a-5-7  0.110 216 1a-5-8  0.107 218 1a-5-10 0.744 219 1a-5-11 0.574 220 1a-5-12 0.0167 221 1a-5-13 0.316 222 1a-5-14 0.078 223 1a-5-15 0.349 224 1a-1-16 0.0101 225 1a-5-17 0.0122 226 1a-5-18 0.166 227 1a-5-19 0.0198 228 1a-5-20 0.106 229 1a-5-21 0.215 230 1a-5-22 0.281 231 1a-5-23 0.197 232 1a-5-24 0.144 233 1a-5-25 0.0864 234 1a-5-26 0.153

TABLE 53 Example No. Compound No. IC₅₀ (μM) Compound No. IC₅₀ (μM) 235 1a-5-27 0.265 236 1a-5-28 0.304 237 1a-5-29 1.32 238 1a-5-30 2.85 239 1a-5-31 0.243 240 1a-5-32 0.0041 241 1a-5-33 0.0131 242 1a-5-34 0.0239 243 1a-5-35 0.0529 244 1a-5-36 0.0165 245 1a-5-37 0.0059 246 1a-5-38 0.0108 247 1a-5-39 0.0035 267 1a-2-66 1.5 1b-2-66 0.011

TABLE 54 Example No. Compound No. IC₅₀ (μM) 252 1-252 0.24 253 1-253 0.000039 254 1-254 0.00063 255 1-255 0.529 256 1-256 0.601 257 1-257 0.776 258 1-258 0.908 259 1-259 0.130 260 1-260 0.159 261 1-260 0.182

The compound of the present invention showed strong activity for inhibiting type IV collagenase.

Industrial Applicability

It is considered that the compound of the present invention is useful to prevent or treat osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, metastasis and invasion of tumor, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis, neurodegengerative disease, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, and gastric ulcer, because the compound of the present invention has strong inhibitory activity against metalloproteinase, especially MMP. 

What is claimed is:
 1. A compound of the formula I:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond; R⁴ is a bond; R⁵ is optionally substituted benzothienyl; Y is —NHOH or —OH; provided R² is a hydrogen atom when Y is —NHOH; an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
 2. A compound of the formula I′:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl; R² is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; and R is halogen; an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
 3. A compound of the formula I″:

wherein R¹ is heteroarylalkyl; R² is a hydrogen atom; and R is halogen; a pharmaceutically acceptable salt thereof, or a hydrate thereof.
 4. A compound according to claim 3, where R¹ is indolylmethyl and R is bromo.
 5. A compound of claim 1, which is:


6. A compound of claim 2, which is:


7. A composition for inhibiting metalloproteinase, comprising a compound of claim
 1. 8. A method of inhibiting the activity of a metalloproteinase, comprising administering an effective amount of a compound of the formula (I) to a subject in need thereof:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond; R⁴ is a bond; R⁵ is optionally substituted thienyl, optionally substituted benzothienyl, or optionally substituted dibenzofuranyl; Y is —NHOH or —OH; provided R² is a hydrogen atom when Y is —NHOH; an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
 9. A method of inhibiting the activity of a metalloproteinase, comprising administering an effective amount of a compound of the formula (I) to a subject in need thereof:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond; R⁴ is a bond; R⁵ is heteroaryl substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, mercapto, alkylthio, cycloalkyl, halogen, carboxy, alkoxycarbonyl, nitro, cyano haloalkyl, aryloxy, unsubstituted amino, guanidino, alkyl, alkenyl, alkynyl, alkanoyl, acyloxy, alkylsulfonyl, phenyl, benzyl, an azo group, and optionally substituted heteroaryl; Y is —NHOH or —OH; provided R² is a hydrogen atom when Y is —NHOH; an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
 10. A method of inhibiting the activity of a metalloproteinase, comprising administering an effective amount of a compound of the formula (I) to a subject in need thereof:

wherein R¹ is optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R² is a hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; R³ is a bond; R⁴ is a bond; R⁵ is optionally substituted heteroaryl; Y is —NHOH or —OH; provided R² is a hydrogen atom when Y is —NHOH; an optically active isomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. 